US9273083B2 - Nickel fluorinating complexes and uses thereof - Google Patents
Nickel fluorinating complexes and uses thereof Download PDFInfo
- Publication number
- US9273083B2 US9273083B2 US14/431,371 US201314431371A US9273083B2 US 9273083 B2 US9273083 B2 US 9273083B2 US 201314431371 A US201314431371 A US 201314431371A US 9273083 B2 US9273083 B2 US 9273083B2
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- aryl
- alkyl
- heteroaryl
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- complex
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- LDSLCQTVZJUCFC-UHFFFAOYSA-M CS(=O)(=O)N1CC[Ni]1(C)S Chemical compound CS(=O)(=O)N1CC[Ni]1(C)S LDSLCQTVZJUCFC-UHFFFAOYSA-M 0.000 description 5
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- SSORPSKSEMECLQ-GEKYYRAYSA-M O=[N+]([O-])C1=C(S(=O)(=O)N([Ag])C2=C(C3=CC=CC=N3)C=CC=C2)C=CC=C1.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(Br)CCCN3(C)C)=CC=C12.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(N4=CC=CC=C4)N(S(=O)(=O)C4=C([N+](=O)[O-])C=CC=C4)C4=C(C=CC=C4)C4=CC=CC=N43)=CC=C12 Chemical compound O=[N+]([O-])C1=C(S(=O)(=O)N([Ag])C2=C(C3=CC=CC=N3)C=CC=C2)C=CC=C1.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(Br)CCCN3(C)C)=CC=C12.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(N4=CC=CC=C4)N(S(=O)(=O)C4=C([N+](=O)[O-])C=CC=C4)C4=C(C=CC=C4)C4=CC=CC=N43)=CC=C12 SSORPSKSEMECLQ-GEKYYRAYSA-M 0.000 description 1
- PMOSJSPFNDUAFY-UHFFFAOYSA-N OCCc(cc1)ccc1Br Chemical compound OCCc(cc1)ccc1Br PMOSJSPFNDUAFY-UHFFFAOYSA-N 0.000 description 1
- PZDYQHMHYAGTJQ-RFGDCJKCSA-N S=S=S=S=S=S=S=S.S=S=S=S=S=S=S=S=S.[H][C@]1(CN=[N+]=[N-])C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CO)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1 Chemical compound S=S=S=S=S=S=S=S.S=S=S=S=S=S=S=S=S.[H][C@]1(CN=[N+]=[N-])C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CO)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1 PZDYQHMHYAGTJQ-RFGDCJKCSA-N 0.000 description 1
- GUUAZPHWAQVGNW-PUVMGAIJSA-N S=S=S=S=S=S=S=S=S.S=S=S=S=S=S=S=S=S=S.[H][C@]1(CN=[N+]=[N-])C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1 Chemical compound S=S=S=S=S=S=S=S=S.S=S=S=S=S=S=S=S=S=S.[H][C@]1(CN=[N+]=[N-])C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1 GUUAZPHWAQVGNW-PUVMGAIJSA-N 0.000 description 1
- HKWGSPWEAYVJNS-OXNUOFCESA-M S=S=S=S=S=S=S=S=S=S.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC([Ni]2(Br)CCCN2(C)C)=CC=C1OCC1CC1 Chemical compound S=S=S=S=S=S=S=S=S=S.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC(Br)=CC=C1OCC1CC1.[H][C@]1(CNC(=O)OC(C)(C)C)C[C@]1([H])C1=CC([Ni]2(Br)CCCN2(C)C)=CC=C1OCC1CC1 HKWGSPWEAYVJNS-OXNUOFCESA-M 0.000 description 1
- OYVGFOYEVGLKNI-VOJFCBSASA-M [H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC(Br)=CC=C12.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(Br)CCCN3(C)C)=CC=C12 Chemical compound [H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC(Br)=CC=C12.[H][C@]12CC[C@]3(C)C(=O)CC[C@@]3([H])[C@]1([H])CCC1=CC([Ni]3(Br)CCCN3(C)C)=CC=C12 OYVGFOYEVGLKNI-VOJFCBSASA-M 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/04—Nickel compounds
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/361—Preparation of halogenated hydrocarbons by reactions involving a decrease in the number of carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
- C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- PET has been used to measure presynaptic accumulation of 18 F-fluorodopa tracer in the dopaminergic regions of the brain (see, for example, Ernst et al., “Presynaptic Dopaminergic Deficits in Lesch-Nyhan Disease” New England Journal of Medicine (1996) 334:1568-1572), but fluorination of other organic compounds has been difficult due to lack of an appropriate fluorination method.
- the present invention provides novel nickel complexes and methods of using these complexes in the fluorination of organic compounds.
- the inventive system is also particularly useful in preparing 18 F-labeled compounds for PET imaging.
- the inventive system relies on utilizing a fluorine source (e.g., a nucleophilic fluorine source) such as a commercially available fluorinating reagent (e.g., tetrabutylammonium difluorophenylsilicate (TBAT)) or a fluoride source comprising water (e.g., containing 18 F which can be produced using a cyclotron).
- a fluorine source e.g., a nucleophilic fluorine source
- a fluorinating reagent e.g., tetrabutylammonium difluorophenylsilicate (TBAT)
- TBAT tetrabutylammonium difluorophenylsilicate
- the present invention is directed to a method of producing a fluorinated organic compound, the method comprising mixing a nickel comprising complex with a flourine source under conditions sufficient to fluorinate the organic compound, thereby providing a fluorinated organic compound.
- the fluorine source is a fluoride source comprising water (e.g., a fluoride source in a mixture is water and acetonitrile).
- the fluoride source contains 18 F fluoride.
- the fluoride source is produced using a cyclotron.
- the fluoride source is produced using a cyclotron in 18 O enriched water.
- the method further comprises an oxidant (e.g., when the fluorinating agent is nucleophilic).
- the fluorinating agent is a nucleophilic fluorinating agent.
- the nucleophilic fluorinating agent is sodium fluoride (NaF), silver fluoride (AgF), tetrabutylammonium fluoride (NH 4 F), substituted tetrabutylammonium fluoride (NR 4 F), cesium fluoride (CsF), potassium fluoride (KF), tetrabutylammonium difluorotriphenylsilicate (TBAT) and XeF 2 .
- the nucleophilic fluorinating agent comprises 18 F or 19 F.
- the method is carried out in the absence of an oxidant (e.g., when the fluorinating agent is electrophilic).
- the fluorinating agent is an electrophilic fluorinating agent.
- the fluorinating agent is selected from the group consisting of N-fluoropyridinium triflate, N-fluoro-2,4,6-trimethylpyridinium triflate, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, N-fluoro-2,6-dichloropyridinium tetrafluoroborate, N-fluoro-2,6-dichloropyridinium triflate, N-fluoropyridinium pyridine heptafluorodiborate, N-fluoropyridinium tetrafluoroborate, an N-fluoroarylsulfonimide (e.g., N-fluorobenzenesulfon
- the reaction further comprises a metal chelator.
- the stabilizer is a crown ether (e.g., 18-crown-6).
- the molar ratio of fluorinating agent to nickel comprising complex is 10:1 or lower (e.g., 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1 or 1:1). In certain embodiments, the molar ratio of oxidant to nickel comprising complex is 10:1 or lower (e.g., 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1 or 1:1).
- the ratio of 18 F-fluorine source to nickel comprising complex is 1:10 or lower (e.g., 1:11, 1:100, 1:1,000, 1:10,000, 1:100,000 or 1:1,000,000). In some embodiments, the ratio of 18 F-fluorine source to nickel comprising complex is 1:10 or lower when the fluorine source is aqueous fluoride (e.g., an 18 F enriched fluoride source). In some embodiments, the nickel comprising complex is a nickel complex of formula (I):
- Ar 1 is heteroaryl (e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole) substituted with n occurrences of R 1 .
- Ar 2 is heteraoaryl (e.g., an N-containing heteroaryl such as quinoline or isoquinoline).
- Ar 2 is aryl (e.g., phenyl) substituted with m occurrences of R 2 .
- the nickel complex of formula (I) is a complex of formula (II):
- a 1 is C 1-6 alkyl, C 3-6 alkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R 3 .
- a 1 is aryl (e.g., phenyl) substituted with o occurrences of R 3 .
- the nickel complex of formula (I) or (II) is a complex of formula (III):
- a 2 is heteroaryl (e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole) substituted with p occurrences of R 4 .
- heteroaryl e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole substituted with p occurrences of R 4 .
- the nickel complex of formula (I), (II) or (III) is a complex of formula (IV):
- m is 0. In some embodiments, n is 0. In some embodiments, p is 0. In some embodiments, o is 1. In some embodiments, R 3 is —NO 2 . In some embodiments, R 3 is substituted at the ortho position relative to the sulfonyl moiety.
- the nickel complex of formula (I), (II), (III) or (IV) is a complex of formula (V):
- S is a pharmaceutically active compound (e.g., a biologically active compound) comprising an aryl, heteroaryl or alkenyl moiety.
- S is a natural product comprising an aryl, heteroaryl or alkenyl moiety.
- S is an optionally substituted aryl comprising substrate (e.g., phenyl). In some embodiments, S is an unsubstituted aryl comprising substrate (e.g., unsubstituted phenyl). In some embodiments, S is a substituted aryl (e.g., a phenyl substituted by one or more substituents). In some embodiments, S is an optionally substituted heteoaryl (e.g., an optionally substituted indolyl or benzyoxazolyl). In some embodiments, S is an optionally substituted C 2-6 alkenyl (e.g., a C 2-6 alkenyl substituted with one or more substituents). In some embodiments, S is selected from one of the following:
- the complex of formula (I), (II), (III), (IV) or (V) is selected from the following:
- the oxidant is a compound of formula (IX):
- X is iodine
- Cy is pyridinyl
- R C is hydrogen
- p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
- a 3 is an aryl group (e.g., phenyl).
- each R F is independently unsubstituted alkyl (e.g., methyl). In some embodiments, each R F is independently —CN. In some embodiments, each R F is independently —OR′′ wherein R′′ is an aliphatic moiety (e.g., methyl). In some embodiments, each R F is independently —N(R′′) 2 wherein R′′ is an aliphatic moiety (e.g., methyl).
- Z is trifluoromethanesulfonate.
- the compound of formula (IX) is selected from the following:
- the fluorinated organic compound comprises an aryl group. In some embodiments, the fluorinated organic compound comprises a heteroaryl group. In some embodiments the fluorinated organic compound comprises an alkenyl group.
- the fluorinated organic compound is selected from the following:
- the fluorinated organic compound is selected from the following:
- the method further comprises a solvent.
- the solvent is a polar aprotic solvent.
- the solvent is acetonitrile.
- the method further comprises adding a salt to the source of fluorine. In some embodiments, the method further comprises adding a salt to the nickel comprising complex. In some embodiments, the method further comprises including a salt in the mixture containing the nickel comprising complex and source of fluorine.
- the salt comprises a chloride, perchlorate, nitrate, phosphate, or sulfate.
- the phosphate comprises a monobasic, dibasic, or tribasic phosphate (e.g., (H 2 PO 4 ) ⁇ , (HPO 4 ) 2 ⁇ , (PO 4 ) 3 ⁇ ).
- the phosphate comprises a tribasic phosphate (e.g., (PO 4 ) 3 ⁇ ).
- the salt comprises a sodium, potassium, or cesium.
- the salt is selected from the following group: NaCl, KClO 4 , KNO 3 , K 3 PO 4 , Na 2 HPO 3 , or Na 2 SO 4 .
- the salt comprises K 3 PO 4 or Na 2 HP 0 3 .
- the salt comprises K 3 PO 4 .
- the method comprises an inert atmosphere. In some embodiments, the method is carried out under anhydrous conditions. In some embodiments, the method comprises cooling (e.g., to 0 ° C. or lower).
- the method comprises a source of energy. In some embodiments, the method comprises heat.
- the fluorinated organic compound is an MRI imaging agent. In some embodiments, the fluorinated organic compound is a PET imaging agent. In some embodiments, the fluorinated organic compound is used as a probe (e.g., a biological NMR probe). In some embodiments, the fluorinated organic compound is a pharmaceutically acceptable compound.
- the present invention is directed to a method of fluorinating an organic compound, the method comprising mixing a nickel comprising complex with a fluoride source comprising water and an oxidant under conditions sufficient to fluorinate the organic compound, thereby providing a fluorinated organic compound.
- the fluorinated organic compound comprises an 18 F labeled organic compound.
- the fluoride source comprising water is a fluoride source in a mixture of water and acetonitrile.
- the salt comprises a chloride, perchlorate, nitrate, phosphate, or sulfate.
- the phosphate comprises a monobasic, dibasic, or tribasic phosphate (e.g., (H 2 PO 4 ) ⁇ , (HPO 4 ) 2 ⁇ , (PO 4 ) 3 ⁇ ).
- the phosphate comprises a tribasic phosphate (e.g., (PO 4 ) 3 ⁇ ).
- the salt comprises a sodium, potassium, or cesium.
- the salt is selected from the following group: NaCl, KClO 4 , KNO 3 , K 3 PO 4 , Na 2 HPO 3 , or Na 2 SO 4 .
- the salt comprises K 3 PO 4 or Na 2 HP 0 3 . In some embodiments, the salt comprises K 3 PO 4 .
- the present invention is directed to a method of making a nickel complex of formula (I), the method comprising treating an organic compound of formula (VI): S—X 1 (VI), with tetramethylethylenediamine and bis(1,5-cyclooctadiene)nickel to provide a nickel complex of formula (VII):
- the method further comprising, treating a nickel complex of formula (VII) with a silver compound of formula (VIII) and A 2 :
- X 1 is halo (e.g., bromo). In some embodiments, X 1 is —OTf.
- the ratio of a compound of formula (VI) to tetramethylethylenediamine is 10:1 or lower (e.g., 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1 or 1:1). In some embodiments, the ratio of a compound of formula (VI) to bis(1,5-cyclooctadiene)nickel is 10:1 or lower (e.g., 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1 or 1:1).
- the ratio of a compound of formula (VII) to a compound of formula (VIII) is 10:1 or lower (e.g., 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1 or 1:1).
- the present invention is directed to methods of making a nickel complex of formula (I), the method comprising treating an organic compound of formula (X): S—B(OR 9 ) 2 (X), with a nickel cubane complex of Formula (XI):
- R 9 is —OH. In some embodiments, R 9 is —OH. In some embodiments, R 9 is methoxy. In some embodiments, R 9 is ethoxy. In some embodiments, R 9 is isopropoxy. In some embodiments, two R 9 groups are taken together as a pinacol. In some embodiments, two R 9 groups are taken together as catechol.
- the nickel complex of formula (XI) is a complex of formula (XII):
- the present invention is directed to a method of making a nickel complex of formula (I), the method comprising treating an organic compound of formula (XIII): S—B(X 1 ) 4 M 1 (XIII), with a nickel cubane complex of Formula (XI):
- X 1 is —F. In some embodiments, X 1 is —Cl. In some embodiments, X 1 is —Br. In some embodiments, X 1 is —I. In some embodiments, X 1 is —OTf. In some embodiments, X 1 is —OTs. In some embodiments, X 1 is —OH.
- M 1 is sodium. In some embodiments, M 1 is potassium.
- the nickel complex of formula (XI) is a complex of formula (XII):
- the present invention is directed to a nickel complex of formula (I):
- Ar 1 is heteroaryl (e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole) substituted with n occurrences of R 1 .
- Ar 2 is heteroaryl (e.g., a N-containing heteroaryl such as quinoline or isoquinoline).
- Ar 2 is aryl (e.g., phenyl) substituted with m occurrences of R 2 .
- the nickel complex of formula (I) is a complex of formula (II):
- a 1 is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R 3 .
- a 1 is aryl (e.g., phenyl) substituted with o occurrences of R 3 .
- the nickel complex of formula (I) or (II) is a complex of formula (III):
- a 2 is heteroaryl (e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole) substituted with p occurrences of R 4 .
- heteroaryl e.g., an N-containing heteroaryl such as pyridine, pyrimidine, imidazole, 1,2,3-triazole or 1,2,4-triazole substituted with p occurrences of R 4 .
- the nickel complex of formula (I), (II) or (III) is a complex of formula (IV):
- m is 0. In some embodiments, n is 0. In some embodiments, p is 0. In some embodiments, o is 1. In some embodiments, R 3 is —NO 2 . In some embodiments, R 3 is substituted at the ortho position relative to the sulfonyl moiety.
- the nickel complex of formula (I), (II), (III) or (IV) is a complex of formula (V):
- S is an optionally substituted aryl comprising substrate (e.g., phenyl). In some embodiments, S is an unsubstituted aryl comprising substrate (e.g., unsubstituted phenyl). In some embodiments, S is a substituted aryl (e.g., a phenyl substituted by one or more substituents). In some embodiments, S is an optionally substituted heteoaryl (e.g., an optionally substituted indolyl or benzyoxazolyl). In some embodiments, S is an optionally substituted C 2-6 alkenyl (e.g., a C 2-6 alkenyl substituted with one or more substituents). In some embodiments, S is selected from one of the following:
- the complex of formula (I), (II), (III), (IV) or (V) is selected from the following:
- the present invention is directed to a method of storing a nickel complex described herein (e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)), the method comprising maintaining the nickel complex in a sealed container for at least 12 hours.
- a nickel complex described herein e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)
- the sealed container is a vial. In some embodiments, the sealed container is an ampule.
- the sealed container is substantially free of dioxygen. In some embodiments, the sealed container contains an inert gas.
- the present invention is directed to a composition comprising a nickel complex described herein (e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)).
- a nickel complex described herein e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)
- the composition further comprises a solvent.
- the solvent is a polar aprotic solvent.
- the solvent is acetonitrile
- the present invention is directed to a reaction mixture comprising a nickel complex described herein (e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)).
- a nickel complex described herein e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)
- the reaction mixture further comprises an oxidant.
- the reaction mixture further comprises a solvent.
- the solvent is a polar aprotic solvent.
- the solvent is acetonitrile.
- the reaction mixture further comprises an inert atmosphere.
- the present invention is directed to a kit comprising a nickel complex described herein (e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)) and a container.
- a nickel complex described herein e.g., a nickel complex of formula (I), (II), (III), (IV) or (V)
- the container is a vial.
- the container is a sealed ampule.
- the container is substantially free of dioxygen. In some embodiments, the container contains an inert gas. In some embodiments, the kit further comprises instructions for use of the nickel complex.
- the kit further comprises an oxidant (e.g., an oxidant described herein).
- the kit further comprises a metal chelator (e.g., a metal chelator described herein such as 18-crown-6).
- inventive compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers.
- inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
- the compounds of the invention are enantiopure compounds.
- mixtures of stereoisomers or diastereomers are provided.
- certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
- the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers.
- this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds.
- a particular enantiomer may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.”
- “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
- Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
- HPLC high pressure liquid chromatography
- Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
- a “bond” refers to a single bond.
- halo and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I).
- aliphatic or “aliphatic group”, as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-10 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms.
- Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
- alkyl refers to saturated, straight—or branched—chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom.
- the alkyl group employed in the invention contains 1-10 carbon atoms.
- the alkyl group employed contains 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms.
- alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.
- alkenyl denotes a monovalent group derived from a Straight—or branched—chain aliphatic moiety having at least one carbon—carbon double bond by the removal of a single hydrogen atom.
- the alkenyl group employed in the invention contains 2-10 carbon atoms.
- the alkenyl group employed in the invention contains 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms or 2 carbon atoms.
- Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
- aryl refers to monocyclic, bicyclic or tricyclic aromatic ring system having a total of five to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
- aryl may be used interchangeably with the term “aryl ring”.
- aryl refers to a monocyclic or polycyclic aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, phenanthrenyl, phenalenyl, and the like, which may bear one or more substituents.
- aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.
- heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 14 ring atoms, wherein the ring atoms include carbon atoms and from one to five heteroatoms.
- heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
- Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
- heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
- Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3- b ]-1,4-oxazin-3(4H)-one.
- a heteroaryl group may be mono- or bicyclic.
- the term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring” any of which terms include rings that are
- heterocyclyl and “heterocyclic ring” are used interchangeably and refer to a monocyclic, bicyclic or tricyclic nonaromatic ring sytem that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one to five heteroatoms, as defined above.
- nitrogen includes a substituted nitrogen.
- the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
- a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
- saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
- heterocycle refers to groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
- a heterocyclyl group may be mono—or bicyclic.
- partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
- the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
- compounds of the invention may contain “optionally substituted” moieties.
- substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
- an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
- stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
- Suitable monovalent substituents on R′ are independently halogen, —(CH 2 ) 0-2 R′′, —(haloR′′), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 0 R′′, —(CH 2 ) 0-2 CH(OR′′) 2 ; —O(haloR′′), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R′′, —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR′′, —(CH 2 ) 0-2 SR′′, —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR′′, —(CH 2 ) 0-2 NHR′′ 2 , —NO 2 ,
- Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on the aliphatic group of R* include halogen, —R′′, —(haloR′′), —OH, —OR′′, —O(haloR′′), —CN, —C(O)OH, —C(O)OR′′, —NH 2 , —NHR′′, —NR′′ 2 , or —NO 2 , wherein each R′′ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R t , —NR t 2 , —C(O)R t , —C(O)OR t , —C(O)C(O)R t , —C(O)CH 2 C(O)R t , —S(O) 2 R t , —S(O) 2 NR t 2 , —C(S)NR t 2 , —C(NH)NR t 2 , or —N(R t )S(O) 2 R t ; wherein each R t is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences
- Suitable substituents on the aliphatic group of R t are independently halogen, —R′′, —(haloR′′), —OH, —OR′′, —O(haloR′′), —CN, —C(O)OH, —C(O)OR′′, —NH 2 , —NHR′′, —NR′′ 2 , or —NO 2 , wherein each R′′ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6 -membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl -[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-
- a “suitable hydroxyl protecting group” as used herein, is well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
- Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2 -(trimethylsilyl) ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-meth
- the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester,
- a “pharmaceutically acceptable form thereof” includes any pharmaceutically acceptable salts, isomers, and/or polymorphs of a palladium complex, or any pharmaceutically acceptable salts, prodrugs and/or isomers of an organic compound, as described below and herein.
- isomers includes any and all geometric isomers and stereoisomers.
- “isomers” include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
- an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.”
- “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
- the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
- Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
- FIG. 1 shows the X-ray crystal structures of nickel(II) aryl complex 1 c.
- FIG. 1A shows the X-ray crystal structure of nickel(II) aryl complex 1 c with hydrogen atoms rendered. The non-hydrogen atoms are depicted with 50% probability ellipsoids.
- FIG. 1B shows additional perspective views where atoms are depicted with 50% probability displacement.
- FIG. 2 shows enantiodiscriminating HPLC traces.
- FIG. 2A shows the enantiodiscriminating HPLC trace of ((1S,2S)-2-(5-bromo-2-(cyclopropylmethoxy) phenyl)cyclopropyl)methanol (S8).
- HPLC method Chiracel ODH column with 5% isopropanol/hexanes eluent for racemic S8 and enantioenriched S8. Percent of total integration listed for each peak.
- FIG. 2A shows the enantiodiscriminating HPLC trace of ((1S,2S)-2-(5-bromo-2-(cyclopropylmethoxy) phenyl)cyclopropyl)methanol (S8).
- HPLC method Chiracel ODH column with 5% isopropanol/hexanes eluent for racemic S8 and enantioenriched S8. Percent of total integration listed for each peak
- FIG. 2B shows the enantiodiscriminating HPLC trace of t-butyl ((( 1 S, 2 S)-2-(5-bromo-2-(cyclopropylmethoxy)phenyl)cyclopropyl)methyl) carbamate (S10).
- HPLC method Chiracel ODH column with 5% isopropanol/hexanes eluent for racemic S10 and enantioenriched S10. The percent of total integration is listed for each peak.
- FIG. 3 shows exemplary radio TLC scans.
- FIG. 3A shows an exemplary radio TLC scan of [ 18 F] 2 a, entry 1 of Table S1. The percent of total integration is listed for [ 18 F] 2 a.
- FIG. 3B shows an examplary radio TLC scan of [ 18 F] 2 b, entry 7 of Table S1. The percent of total integration is listed for [ 18 F] 2 b.
- FIG. 3C shows an exemplary radio TLC scan of [ 18 F] 2 c, entry 14 of Table S1. The percent of total integration is listed for [ 18 F] 2 c.
- FIG. 3D shows an exemplary radio TLC scan of [ 18 F] 2 d, entry 23 of Table S1. The percent of total integration listed for [ 18 F] 2 d.
- FIG. 3A shows an exemplary radio TLC scan of [ 18 F] 2 a, entry 1 of Table S1. The percent of total integration is listed for [ 18 F] 2 a.
- FIG. 3B shows an examplary radio TLC scan of [
- FIG. 3E shows an exemplary radio TLC scan of [ 18 F] 2 e, entry 25 of Table S1. The percent of total integration is listed for [ 18 F] 2 e.
- FIG. 3F shows an exemplary radio TLC scan of [ 18 F] 2 f, entry 34 of Table S1. The percent of total integration listed for [ 18 F] 2 f.
- FIG. 3G shows an exemplary radio TLC scan of [ 18 F] 2 g, entry 39 of Table S1. The percent of total integration is listed for [ 18 F] 2 g.
- FIG. 3H shows an exemplary radio TLC scan of [ 18 F] 2 h, entry 44 of Table S1. The percent of total integration is listed for [ 18 F] 2 h.
- FIG. 31 shows an exemplary radio TLC scan of [ 18 F] 2 i, entry 51 of Table S1. The percent of total integration is listed for [ 18 F] 2 i.
- FIG. 3J shows an exemplary radio TLC scan of [ 18 F] 2 k, entry 63 of Table S1. The percent of total integration is listed for [ 18 F] 2 k.
- FIG. 3K shows an exemplary radio TLC scan of [ 18 F] 2 l, entry 71 of Table S1. The percent of total integration is listed for [ 18 F] 2 l.
- FIG. 4 shows the characterization of 18 F-labeled molecules. All 18 F-labeled molecules were characterized by comparing the HPLC trace (measured by radioactivity) of the crude reaction mixture to the HPLC trace (measured by UV) of the corresponding authentic 19 F-containing reference sample.
- An Agilent Eclipse XDB-C18, 5 ⁇ m, 4.6 ⁇ 150 mm HPLC column was used for analytical HPLC analysis. Analytical HPLC used the following mobile phases: 0.1% CF 3 CO 2 H in water (A) 0.1% CF 3 CO 2 H in acetonitrile (B). Program: 95% (A) and 5% (B) for 10 minutes.
- FIG. 4A shows the characterization of [ 18 F] 2 a. 280 nm UV trace (top) of authentic sample ( 2 a ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 a , and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4B shows the characterization of [ 18 F] 2 b. 280 nm UV trace (top) of authentic sample ( 2 b ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 b, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4A shows the characterization of [ 18 F] 2 a. 280 nm UV trace (top) of authentic sample ( 2 a ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 b, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4C shows characterization of [ 18 F] 2 c. 280 nm UV trace (top) of authentic sample ( 2 c ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 c, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4D shows the characterization of [ 18 F] 2 d. 280 nm UV trace (top) of authentic sample ( 2 d ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 d, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4E shows the characterization of [ 18 F] 2 e.
- FIG. 4F shows the characterization of [ 18 F] 2 f. 280 nm UV trace (top) of authentic sample ( 2 f ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 f, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4G shows characterization of [ 18 F] 2 g.
- FIG. 4H shows the characterization of [ 18 F] 2 h.
- 280 nm UV trace (top) of authentic sample ( 2 h ) radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 h, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 41 shows the characterization of [ 18 F] 2 i.
- FIG. 4J shows the characterization of [ 18 F] 2 j. 280 nm UV trace (top) of authentic sample ( 2 j ), radioactivity trace of the reaction mixture (middle) containing [ 18 F] 2 j, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 4K shows the characterization of [ 18 F] 2 k.
- FIG. 4L shows the characterization of [ 18 F] 21 .
- 280 nm UV trace (top) of authentic sample ( 21 ) radioactivity trace of the reaction mixture (middle) containing [ 18 F]2 l, and 280 nm UV trace (bottom) of the reaction mixture.
- FIG. 5 shows the X-ray structure of nickel complex 1 x.
- FIG. 5A shows the X-ray structure of nickel complex 1 x without the rendering of the ligand backbone to enable a clear view of the cubane cluster.
- FIG. 5B shows the X-ray structure of complex 1 x with complete rendering of the ligand backbone to enable a view of the entire complex and potential hydrogen bonding interactions.
- the present invention novel nickel complexes, a method for producing these complexes and their methods of use. These complexes are useful in fluorinating an organic compound (e.g., utilizing a nucleophilic fluorine source). In particular, the inventive complexes are useful in labelling a compound with 18 F for positron emission tomography (PET). Also described herein are compositions, reaction mixtures and kits comprising these nickel complexes and fluorinated organic compounds.
- the present invention provides novel nickel complexes.
- the complex comprises one or more bidentate or tridentate ligands.
- the present invention is directed to a nickel complex of formula (I):
- the nickel complex of formula (I) is a complex of formula (II):
- the nickel complex of formula (I) or (II) is a complex of formula (III):
- the nickel complex of formula (I), (II) or (III) is a complex of formula (IV):
- the nickel complex of formula (I), (II), (III) or (IV) is a complex of formula (V):
- the inventive nickel complexes are typically prepared as described in the methods below.
- the method of making a nickel complex of formula (I) comprises treating an organic compound of formula (VI): S—X 1 (VI) with tetramethylethylenediamine and bis(1,5-cyclooctadiene)nickel to provide a nickel complex of formula (VII):
- the method further comprising, treating a nickel complex of formula (VII) with a silver compound of formula (VIII) and A 2 :
- X 1 is halo (e.g., bromo). In some embodiments, X 1 is —OTf.
- the method of making a nickel complex of formula (I) comprises treating an organic compound of formula (X): S—B(OR 9 ) 2 (X), with a nickel cubane complex of formula (XI):
- R 9 is —OH. In some embodiments, R 9 is —OH. In some embodiments, R 9 is methoxy. In some embodiments, R 9 is ethoxy. In some embodiments, R 9 is isopropoxy. In some embodiments, two R 9 groups are taken together as a pinacol. In some embodiments, two R 9 groups are taken together as catechol.
- the method of making a nickel complex of formula (I) comprises treating an organic compound of formula (XIII): S—B(X 1 ) 4 M 1 (XIII), with a nickel cubane complex of formula (XI):
- X 1 is —F. In some embodiments, X 1 is —Cl. In some embodiments, X 1 is —Br. In some embodiments, X 1 is —I. In some embodiments, X 1 is —OTf. In some embodiments, X 1 is —OTs. In some embodiments, X 1 is —OH.
- M 1 is sodium. In some embodiments, M 1 is potassium.
- the process for utilizing the nickel complexes described herein utilizes a source of fluorine. Fluorine occurs naturally as fluorine- 19 ( 19 F). Fluorine- 18 ( 18 F) is a radioisotope of fluorine.
- the source of fluorine is a fluoride source comprising water (i.e., negatively charged fluoride ions present in a mixture of water and acetonitrile).
- the fluoride source may contain a particular isotope of fluorine (e.g., 18 F).
- the fluoride source contains 18 F fluoride (i.e., transfers an 18 F fluorine substituent to the organic compound).
- reaction of the 18 F fluoride source in the inventive process provides a fluorinated 18 F-labeled organic compound.
- the fluoride source comprising water (e.g., the aqueous fluoride source contains 18 F) is produced using a cyclotron. In some embodiments, the fluoride source comprising water is produced using a cyclotron in 18 O enriched water.
- the source of fluorine is a fluorinating agent.
- the fluorinating agent is a nucleophilic fluorinating agent.
- the methods described herein further comprise an oxidant as described herein.
- the fluorinating agent is commercially available.
- the nucleophilic fluorinating agent is an inorganic fluorinating agent.
- the nucleophilic fluorinating agent is sodium fluoride (NaF), silver fluoride (AgF), tetrabutylammonium fluoride (NH 4 F), substituted tetrabutylammonium fluoride (NR 4 F), cesium fluoride (CsF), potassium fluoride (KF), tetrabutylammonium difluorotriphenylsilicate (TBAT) and XeF 2
- the nucleophilic fluorinating agent comprises 18 F or 19 F.
- the fluorinating agent is an electrophilic fluorinating agent.
- the electrophlic fluorinating agents include, but are not limited to, N -fluoropyridinium triflate, N-fluoro-2,4,6-trimethylpyridinium triflate, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, N-fluoro-2,6-dichloropyridinium tetrafluoroborate, N-fluoro-2,6-dichloropyridinium triflate, N-fluoropyridinium pyridine heptafluorodiborate, N-fluoropyridinium tetrafluoroborate, N-fluoropyridinium triflate, N-fluoroarylsulfonimide (e.g., N-fluorobenzenesulfonimide) and N-chloromethyl-N′-fluorotriethylene
- the fluorinating agent is Selectfluor®. In certain embodiments, the fluorinating agent is N-fluoropyridinium triflate. In certain embodiments, the fluorinating agent is N-fluoro-2,4,6-trimethylpyridinium triflate. In certain embodiments, the fluorinating agent is N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate. In certain embodiments, the fluorinating agent is N-fluoro-benzenesulfonimide. In certain embodiments, the fluorinating agent is xenon difluoride.
- the fluorinating agent is N-chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor®).
- the electrophilic fluorinating agent comprises 18 F or 19 F.
- the fluorinating agent may contain a particular isoptope of fluorine.
- the fluorinating agent contains 19 F (i.e., transfers an 19 F fluorine substituent to the organic compound).
- reaction of the 19 F fluorinating agent in the inventive process provides a fluorinated 19 F-labeled organic compound.
- the fluorinating agent contains 18 F (i.e., transfers an 18 F fluorine substituent to the organic compound).
- reaction of the 18 F fluorinating agent in the inventive process provides a fluorinated 18 F-labeled organic compound.
- the fluorinating agent is labeled with a mixture of 18 F and 19 F.
- reaction of the fluorinating agent with a mixture of 19 F and 18 F in the inventive process provides a mixture of fluorinated 19 F-labeled organic compound and fluorinated 18 F-labeled organic compound.
- the portion of each of 19 F and 18 F in the mixture is known. Any of the above fluorinated agents may be labeled with 19 F or 18 F.
- the invention provides a process for fluorinating substrate (e.g., an organic substrate) using a nickel complex.
- the substrate has a particular substituent (i.e., the nickel complex) that is replaced with the fluoride from the complex.
- the substrate utilized in the inventive process includes, but is not limited to, small organic molecules and/or large organic molecules.
- a small organic molecule include any molecule having a molecular weight of less than 1000 g/mol, of less than 900 g/mol, of less than 800 g/mol, of less than 700 g/mol, of less than 600 g/mol, of less than 500 g/mol, of less than 400 g/mol, of less than 300 g/mol, of less than 200 g/mol or of less than 100 g/mol.
- a large organic molecule include any molecule of between 1000 g/mol to 5000 g/mol, of between 1000 g/mol to 4000 g/mol, of between 1000 g/mol to 3000 g/mol, of between 1000 g/mol to 2000 g/mol, or of between 1000 g/mol to 1500 g/mol.
- Substrates include, but are not limited to, aryl compounds, heteroaryl compounds, carbocyclic compounds, heterocyclic compounds, aliphatic compounds, heteroaliphatic compounds, as well as polymers, peptides, glycopeptides, and the like.
- the substrate is an optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted aryl, or optionally substituted heteroaryl compound.
- the substrate is an aryl-containing compound.
- a substrate is a polymer
- a substrate is a peptide
- a substrate is biologically active.
- the substrate is an agrochemical.
- the substrate is an insecticide or a pheromone of insect origin.
- the substrate is pharmaceutical agent.
- the pharmaceutical agent is an anti-emetic, anti-coagulant, anti -platelet, anti-arrhythmic, anti-herpertensive, anti-anginal, a lipid-modifying drug, sex hormone, anti-diabetic, antibiotic, anti-viral, anti-fungal, anti-cancer, immunostimulant, immunosuppressant, anti-inflammatory, anti-rheumatic, anesthetic, analgesic, anticonvulsant, hypnotic, anxiolytic, anti-psychotic, barbituate, antidepressant, sedative, anti-obesity, antihistime, anti-eleptic, anti-manic, opioid, anti-Parkinson, anti-Alzheimers, anti-dementia, an anti-substance dependance drug, cannabinoid, 5 HT-3 antagonist, monoamine oxidase inhibitor (MAOI), selective serotonin reuptake inhibitor
- MAOI monoamine oxida
- the pharmaceutical agent is a psychotropic agent.
- the pharmaceutical agent is any pharmaceutical agent approved by the United States Food and Drug Administration (FDA) for administration to a human (see, e.g., www.accessdata.fda.gov/scripts/cder/drugsatfda).
- FDA United States Food and Drug Administration
- the pharmaceutical agent is an antibiotic. In certain embodiments, the pharmaceutical agent is a lipid modifying drug. In certain embodiments, the pharmaceutical agent is a CNS drug (i.e., drug acting on the Central Nervous System).
- CNS drugs include, but are not limited to, hypnotics, anxiolytics, antipsychotics, barbituates, antidepressants, antiobesity, antihistimes, antieleptics, antimanics, opioids, analgesics, anti -Parkinson, anti-Alzheimers, anti-dementia, anti-substance dependance drugs, cannabinoids, 5HT-3 antagonists, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) and stimulants.
- MAOIs monoamine oxidase inhibitors
- SSRIs selective serotonin reuptake inhibitors
- Exemplary pharmaceutical agents such as antibiotics, lipid modifying agents and CNS agents are provided in International Application Nos. PCT/US2010/020544; PCT/US2010/020540 and PCT/US2010/041561, each of which is incorporated by reference herein in its entirety.
- the substrate after fluorination, is biologically active. In certain embodiments, the substrate, prior to fluorinated, is also biologically active.
- the process provides after fluorination of the substrate a known biologically active fluorinated compound, such as a fluorinated agrochemical or fluorinated pharmaceutical agent.
- the process provides after fluorination, the following compounds:
- compositions comprising a nickel complex described herein, including a reaction mixture, e.g., a reaction mixture that is present during a method or process described herein.
- the process comprises mixing a nickel comprising complex described herein and a substrate with a fluorinating agent and an oxidant (e.g., a compound of formula (IX)) under conditions sufficient to fluorinate the substrate to thereby provide a fluorinated organic compound.
- a fluorinating agent and an oxidant e.g., a compound of formula (IX)
- the nickel complex can be bound to a solid support.
- the method further comprises a solvent.
- the solvent is an organic solvent.
- the solvent is an aprotic solvent.
- Exemplary organic solvents include, but are not limited to, benzene, toluene, xylenes, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, ethyl ether, tetrahydrofuran, methylene chloride, dichloroethane and chloroform, or a mixture thereof.
- the solvent is acetonitrile.
- the solvent is acetonitrile.
- the reaction further comprises heating. In certain embodiments, the reaction further comprises cooling (e.g., to 0 ° C. or lower). In certain embodiments, the reaction takes place under an inert atmosphere (e.g, an atmosphere of an inert gas such as nitrogen or argon). In certain embodiments, the reaction takes place under anhydrous conditions (e.g., conditions that are substantially free of water).
- an inert atmosphere e.g, an atmosphere of an inert gas such as nitrogen or argon
- anhydrous conditions e.g., conditions that are substantially free of water.
- the fluorination reaction is regiospecific.
- Organofluorine compounds are emerging as chemical specialties of significant and increasing commercial interest. A major driver has been the development of fluorine -containing bio-active molecules for use as medicinal and plant-protection agents. Other new applications involving organofluorine chemistry are in the synthesis of liquid crystals, surface active agents, specialty coatings, reactive dyes, and even olefin polymerization catalysts.
- 19 F-fluorinated organic compounds may be useful for magnetic resonance imaging (MRI) technology.
- MRI magnetic resonance imaging
- MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures in MRI. Contrast agents alter the relaxation times of tissues and body cavities where they are present, which depending on the image weighting can give a higher or lower signal. Fluorine-containing constrast agents may be especially useful due to the lack of fluorine chemistry in the human body. This could, for example provide a detailed view of acidic regions, such as those containing cancer cells.
- 19 F-labeled MRI contrast agents may add chemical sensitivity to MRI and could be used to track disease progression without the need to take tissue or fluid samples.
- 19 F-fluorinated organic compounds may also be useful as probes for nuclear magnetic resonance (NMR) spectroscopy.
- Fluorine has many advantages as a probe for NMR spectroscopy of biopolymers.
- 19 F has a spin of one-half, and its high gyromagnetic ratio contributes to its high sensitivity (approximately 83% of the sensitivity of 1 H). It also facilitates long-range distance measurements through dipolar-dipolar coupling.
- the near-nonexistence of fluorine atoms in biological systems enables 19 F NMR studies without background signal interference.
- the chemical shift of 19 F has been shown to be very sensitive to its environment.
- PET positron-emission tomography
- PET tracers are molecules which incorporate a PET-active nucleus and can therefore be visualized by their positron emission in the body.
- the fluorine isotope 18 F is the most common nucleus for PET imaging because of its superior properties to other nuclei.
- the 18 F radioisotope has a half-life of 109 minutes.
- the short half-life dictates restrictions on chemical synthesis of PET tracers, because introduction of the fluorine atom has to take place at a very late stage of the synthesis to avoid the unproductive decay of 18 F before it is injected into the body.
- Fluoride ion is the most common reagent to introduce 18 F but the specific chemical properties of the fluoride ion currently limit the available pool of PET tracers. Due to the narrow functional group compatibility of the strongly basic fluoride ion, only a limited set of chemical reactions can be employed for fluorination, and hence the synthesis of PET tracers is limited to fairly simple molecules such as FDG.
- the field of PET imaging would benefit from the availability of a new method that is capable of introducing radiolabeled fluoride into structurally more complex organic molecules.
- An easy access to drug-based PET tracers would simplify determining the fate of such drugs in the body and thereby help to identify and understand their mode of action, bioavailability and time -dependent biodistribution.
- the complexes described herein including a nickel complex described herein can be used to produce fluorinated organic compounds (e.g., a biologically active fluorinated organic compound).
- fluorinated organic compounds e.g., a biologically active fluorinated organic compound.
- the compositions delineated herein may include these fluorinated organic compounds described herein, such as fluorinated pharmaceutical agents, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
- the fluorinated compound is made by a method described herein.
- pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
- Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-pol
- Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
- a complex or compound described herein e.g., a nickel complex described herein, an organic compound, a source of fluorine (e.g., a source of fluorine described herein such as a fluoride source comprising water or a fluorinating agent such as a fluorinating agent described herein), or a fluorinated compound, such as a fluorinated pharmaceutical agent) may be provided in a kit.
- the kit includes (a) a compound used in a method described herein, and, optionally (b) informational material.
- the kit further includes an oxidant (e.g., an oxidant described herein).
- the kit further includes a metal chelator (e.g., a metal chelator described herein such as 18-crown-6).
- a metal chelator e.g., a metal chelator described herein such as 18-crown-6.
- the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein.
- the nickel complex is bound to a solid support.
- the informational material of the kits is not limited in its form.
- the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth.
- the informational material can include instructions to administer a compound described herein in a suitable manner to perform the methods described herein, .
- the informational material of the kits is not limited in its form.
- the informational material e.g., instructions
- the informational material is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet.
- the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording.
- the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein.
- the informational material can also be provided in any combination of formats.
- the components of the kit are stored under inert conditions (e.g., under Nitrogen or another inert gas such as Argon). In some embodiments, the components of the kit are stored under anhydrous conditions (e.g., with a desiccant). In some embodiments, the components are stored in a light blocking container such as an amber vial.
- inert conditions e.g., under Nitrogen or another inert gas such as Argon.
- anhydrous conditions e.g., with a desiccant
- the components are stored in a light blocking container such as an amber vial.
- a compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that a compound described herein be substantially pure and/or sterile.
- the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred.
- reconstitution generally is by the addition of a suitable solvent.
- the solvent e.g., sterile water or buffer, can optionally be provided in the kit.
- the kit can include one or more containers for the composition containing a compound described herein.
- the kit contains separate containers, dividers or compartments for the composition and informational material.
- the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet.
- the separate elements of the kit are contained within a single, undivided container.
- the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
- the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit forms of a compound described herein.
- the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
- Benzene, benzene-d 6 , diethyl ether, toluene, pentane, dioxane and THF were distilled from deep purple sodium benzophenone ketyl.
- Methylene chloride-d 2 was dried over CaH 2 and vacuum-distilled.
- Acetonitrile and acetonitrile-d 3 were dried over P 2 O 5 and vacuum-distilled.
- Pyridine and tetramethylethylenediamine (TMEDA) were dried over CaH 2 and distilled.
- DMSO was distilled from sodium triphenylmethanide and stored over 3 ⁇ sieves.
- Acetone was distilled over B 2 O 3 . MeOH was degassed at ⁇ 30 ° C.
- NMR spectra were recorded on either a Varian Unity/Inova 600 spectrometer operating at 600 MHz for 1 H acquisitions, a Varian Unity/Inova 500 spectrometer operating at 500 MHz and 125 MHz for 1 H and 13 C acquisitions, respectively, a Varian Mercury 400 spectrometer operating at 375 MHz and 101 MHz for 19 F and 13 C acquisitions, respectively, or a Varian Mercury 300 spectrometer operating at 100 MHz for 11 B acquisitions.
- TEDA tetramethylethylenediamine
- aryl bromide 0.717 mmol, 1.00 equiv
- toluene 4 mL
- bis(cyclooctadiene)nickel(0) Ni(COD) 2
- Pentane (16 mL) was added to the mixtures and the corresponding nickel complexes were collected on a frit. The solid was washed with pentane (3 ⁇ 5 mL) and dried in vacuo.
- the solid was extracted with CH 2 C 1 2 (5 mL) and the solution was filtered through a pad of Celite on a glass frit and the filtered cake was extracted further with dichloromethane (3 ⁇ 1 mL).
- the combined filtrate was concentrated in vacuo and the resulting residue was redissolved in dichloromethane and the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo.
- the resulting residue was purified by recrystallization (CH 2 Cl 2 /pentane) or chromatography on silica gel.
- reaction mixture Upon the addition of DBU, the reaction mixture turned yellow. The reaction mixture was warmed to 23 ° C. and stirred for 15 hours. The reaction mixture was poured into H 2 O (75 mL) in a separatory funnel. CHCl 3 (75 mL) was added and the funnel was shaken and the organic phase collected. The aqueous phase was extracted from with CHCl 3 (2 ⁇ 50 mL). All organic phases were combined and washed with brine (50 mL), dried with Na 2 SO 4 , and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5-10% EtOAc in hexanes (v/v) to afford 3.89 g of the title compound as a colorless solid (98% yield).
- Racemic S8 was synthesized using the above procedures omitting the addition of (4R,5R)-2-butyl-N,N,N′,N′-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide. Absolute stereochemistry was assigned by analogy.
- the reaction mixture was poured into a separatory funnel with saturated NH 4 Cl solution (40 mL). The funnel was shaken and the organic phase collected. The aqueous phase was extracted from with diethyl ether (3 ⁇ 75 mL). The organic phases were combined and washed with saturated NaHCO 3 (100 mL) and brine (100 mL), dried with MgSO 4 , and concentrated in vacuo. The residue was dissolved in DMF (30 mL) and NaN 3 (1.88 g, 28.9 mmol, 4.00 equiv) was added. The reaction mixture was heated at 60 ° C. for 1 hour. The reaction mixture was cooled and poured into 60 mL of water.
- (S)-N-(tert-butyloxycarbonyl)-2-bromo-4,5-dihydroxyphenylalanine methyl ester was prepared by a published method. To the mixture of (S)-N-(tert-butyloxycarbonyl)-2-bromo -4,5-dihydroxyphenylalanine methyl ester (8.00 g, 20.5 mmol, 1.00 equiv) and Et 3 N (5.72 ml, 4.15 g, 164 mmol, 2.00 equiv) in a round-bottom flask in PhMe (100 ml) was added Boc 2 O (3.86 g, 4.11 mL, 17.7 mmol, 3.00 equiv) in one portion.
- nickel (II) aryl complex 1 a 40 mg, 0.62 mmol, 1.0 equiv
- TBAT tetrabutylammonium difluorotriphenylsilicate
- oxidant (6) 50 mg, 0.93 mmol, 1.5 equiv
- the vial was taken out of the glove box, and immersed in an ice bath at 0 ° C. for 5 minutes.
- To the reaction mixture was added quickly pre-cooled acetonitrile (4 mL) at 0 ° C.
- Nickel aryl complex 1 e 50 mg, 0.077 mmol, 1.0 equiv
- 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (33 mg, 0.092 mmol, 1.5 equiv) were placed in a 20 mL vial.
- acetonitrile (4 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C.
- Nickel aryl complex 1f (30 mg, 0.042 mmol, 1.0 equiv) and Selectfluor® (18 mg, 0.050 mmol, 1.2 equiv) were placed in a 20 mL vial.
- To the reaction mixture was added quickly acetonitrile (3 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C.
- the solution was subsequently concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with hexane/EtOAc 4:1 (v/v) to afford 5.6 mg of the title compound as a colorless solid (55% yield).
- Nickel aryl complex 1 l (30 mg, 0.040 mmol, 1.0 equiv) and Selectfluor® (17 mg, 0.048 mmol, 1.2 equiv) were placed in a 20 mL vial.
- To the reaction mixture was added quickly acetonitrile (3 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C.
- the solution was subsequently concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with Et 2 O/CH 2 Cl 2 2:1 (v/v) to afford 4.0 mg of the title compound as a colorless solid (36% yield).
- Rf 0.88 (Et 2 O/CH 2 Cl 2 2:1 (v/v)).
- Nickel acetate tetrahydrate (0.280 g, 1.23 mmol) was added, and the flask was evacuated under vacuum and backfilled with nitrogen.
- Distilled pyridine (16 ml) was added and the resulting dark blue solution was stirred.
- the solution was added to the nickel reaction mixture dropwise via syringe followed by a pyridine wash (1 ⁇ 1 ml). The mixture became greenish-yellow, and a colorless precipitate formed. The mixture was stirred for 1 h at ambient temperature, and the mixture was concentrated in vacuo (50 ° C. waterbath). The crude green-orange residue was dried in vacuo over 12 h. To the crude solid was added 10 ml THF, and the solution was filtered through Celite. The flask was rinsed (2 ⁇ 3 ml THF) and transferred to the filter pad successively. A turbid green solution was obtained.
- This solution was filtered through a second pad of Celite, rinsing with THF (1 ⁇ 2 ml) to obtain a homogeneous green solution.
- Water 0.1 ml was added with vigorous stirring, effecting precipitation of a large amount of turquoise solid and a yellow supernatant.
- Additional water 0.4 ml was added with stirring, and the entire mixture was transferred to a 20 ml glass vial with a THF wash (1 ⁇ 1 ml). The mixture was centrifuged, and the yellow supernatant was decanted leaving a turquoise solid.
- THF (6 ml) was added, the solution was mixed and centrifuged, and the colorless supernatant decanted.
- the mixture was sonicated briefly, leading to a yellow-green solution. Following 20 min, the solution was transferred to a 20 ml glass vial, and pentane (16 ml) was added dropwise with stirring, resulting in a biphasic system. The pentane layer was decanted, and ether (18 ml) was added. The mixture was stirred vigorously, leading to precipitation of a yellow solid. The mixture was centrifuged, the supernatant decanted, and the resulting residue was dried in vacuo. Minimal dicholoromethane was added to the residue, leading to the production of a quantity of orange solid.
- the solid was triturated with pentane (5 ⁇ 5 ml) and dried in vacuo.
- the solid was dissolved in dichloromethane, filtered through Celite, reduced in volume to approximately 1 ml in vacuo, following which pentane (15 ml) was added dropwise to the stirred mixture leading to formation of a yellow precipitate.
- the vial was centrifuged, and the organic layer was decanted.
- the residual yellow solid was sonicated with pentane (10 ml), centrifuged, the organic layer was decanted, and the process repeated a second time.
- the residual yellow solid was dried in vacuo to yield the product 1 c as a yellow solid (52.0 mg, 96%).
- No-carrier-added [ 18 F]fluoride was produced from water 97% enriched in 18 O (Sigma-Aldrich®) by the nuclear reaction 18 O(p,n) 18 F using a Siemens Eclipse HP cyclotron and a silver-bodied target at MGH Athinoula A. Martinos Center for Biomedical Imaging.
- the produced [ 18 F]fluoride in water was transferred from the cyclotron target by helium push.
- LC Liquid chromatographic analysis
- Agilent 1100 series HPLCs connected to a Carol and Ramsey Associates Model 105-S radioactivity detector.
- An Agilent Eclipse XDB-C18, 5 ⁇ m, 4.6 ⁇ 150 mm HPLC column was used for analytical analysis and a Waters BondapakTM C18, 10 ⁇ m, 125 ⁇ 7.6 ⁇ 300 mm HPLC was used for preparative HPLC.
- Analytical HPLC used the following mobile phases: 0.1% CF 3 CO 2 H in water (A) 0.1% CF 3 CO 2 H in acetonitrile (B). Program: 50% (B) for 2 minutes then a gradient 50-95% (B) over 8 minutes.
- Preparative HPLC used the following mobile phases: 0 .
- the solution became immediately pink or red or yellow depending on nickel complexes and then became colorless within 5 to 10 seconds.
- a capillary tube was then used to spot the solution on a silica gel TLC plate.
- the TLC plate was emerged in an appropriate organic solvent mixture.
- the TLC plate was scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner. Results are shown on Table S1 (See also FIG. 3 ).
- a portion of aqueous [ 18 F]fluoride solution (as specified on Table S2) obtained from a cyclotron was added to an acetonitrile solution (0.5 mL) which contained 1 mg of 18-cr-6.To this solution was added a portion of saturated aqueous solution of a salt (as specified on Table S2), and the resulting solution was added quickly to a septum-capped vial containing 1.0 mg nickel complex 1 and 1.0 equiv of 6 (compared to 1). The solution became immediately pink or red or yellow depending on nickel complexes and then became colorless within 5 to 10 seconds. A capillary tube was then used to spot the solution on a silica gel TLC plate. The TLC plate was emerged in an appropriate organic solvent mixture.
- the TLC plate was scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner. As shown on Table S2, a number of inorganic additives led to an increase in radiochemical yield. Most notably, K 3 PO 4 doubled the radiochemical yield for the fluorination of an indole nickel complex.
- Radiochemical yield was determined by multiplying the percentage of radioactivity in the solution and the relative peak integrations of a radio TLC scan. After spotting the solution on a silica gel TLC plate, the remaining solution was transferred to the other vial. The radioactivity of the solution was measured in an ion chamber and the amount of radioactivity left on the walls of the initial vial was measured. After radio TLC quantification, the radiochemical yield was determined by multiplying the product quantified during TLC by the fraction of radioactivity in solution (typically 70-85%, see also FIG. 4 ).
Abstract
Description
-
- Ar1 is aryl or heteroaryl substituted with n occurrences of R1;
- Ar2 is aryl or heteroaryl substituted with m occurrences of R2;
- A1 is C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)-R6, C(O)—R6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R3;
- A2 is an N-heterocyclic carbene, phosphine, phosphate or heteroaryl substituted with p occurrences of R4;
- S is a substrate wherein the substrate is linked through an aryl, heteroaryl or alkenyl moiety present in the substrate;
- each R1, R2, R3 and R4 is independently halo, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with 0-3 occurrences of R8;
- R6 is C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)O—C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R7 is independently C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)—C1-6 alkyl, —C(O)O—C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R8 is independently halo, C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, C3-7 cycloalkyl, C1-6 alkyl-amine, —C(O)—C1-6 alkyl, —C(O)O—C1-6 alkyl, C0-6 alkyl-NHR7, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl or wherein two adjacent R8 moieties, taken together with the atoms to which they are attached, form a C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl group, wherein each alkyl, alkoxy, alkenyl, cycloalkyl, aryl; and
- m, n, o and p are each independently an integer from 0-5.
-
- X is a halogen
- A3 is an aryl or heteroaryl group;
- Cy taken together with the nitrogen atom to which it is attached forms a heterocyclyl or heteroaryl ring;
- each occurrence of RF is independently halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR″; —C(=O)R″; —CO2R″; —CN; —SCN; —SR″; —SOR″; —SO2R″; —NO2; —N(R″)2; —NHC(O)R″; or —C(R″)3; wherein each occurrence of R″ is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
- Z is an anion.
S—X1 (VI),
with tetramethylethylenediamine and bis(1,5-cyclooctadiene)nickel to provide a nickel complex of formula (VII):
the method further comprising, treating a nickel complex of formula (VII) with a silver compound of formula (VIII) and A2:
to provide a nickel complex of formula (I), wherein
X1 is a leaving group; and
Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I).
S—B(OR9)2 (X),
with a nickel cubane complex of Formula (XI):
-
- R9 is defined as halo, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, —OH, —OR6, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl, or heterocyclyl can be further substituted with 0-3 occurrences of R8; and
Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I).
- R9 is defined as halo, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, —OH, —OR6, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl, or heterocyclyl can be further substituted with 0-3 occurrences of R8; and
S—B(X1)4M1 (XIII),
with a nickel cubane complex of Formula (XI):
-
- X1 is a leaving group;
- M1 is an alkali metal; and
- Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I).
-
- Ar1 is aryl or heteroaryl substituted with n occurrences of R1;
- Ar2 is aryl or heteroaryl substituted with m occurrences of R2;
- A1 is C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R3;
- A2 is an N-heterocyclic carbene, phosphine, phosphate or heteroaryl substituted with p occurrences of R4;
- S is a substrate wherein the substrate is linked through an aryl, heteroaryl or alkenyl moiety present in the substrate;
- each R1, R2, R3 and R4 is independently halo, C1-6 alkyl, Ci-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with 0-3 occurrences of R8;
- R6 is C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)O—C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R7 is independently C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)—C1-6 alkyl, —C(O)O—C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R8 is independently halo, C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, C3-7 cycloalkyl, C1-6 alkyl-amine, —C(O)—C1-6 alkyl, —C(O)O—C1-6 alkyl, C0-6 alkyl-NHR7, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl or wherein two adjacent R8 moieties, taken together with the atoms to which they are attached, form a C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl group, wherein each alkyl, alkoxy, alkenyl, cycloalkyl, aryl; and
- m, n, o and p are each independently an integer from 0-5.
-
- Ar1 is aryl or heteroaryl substituted with n occurrences of R1;
- Ar2 is aryl or heteroaryl substituted with m occurrences of R2;
- A1 is C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R3;
- A2 is an N-heterocyclic carbene, phosphine, phosphate or heteroaryl substituted with p occurrences of R4;
- S is a substrate wherein the substrate is linked through an aryl, heteroaryl or alkenyl moiety present in the substrate;
- each R1, R2, R3 and R4 is independently halo, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, NO2, —OH, —OR6, aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with 0-3 occurrences of R8;
- R6 is C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)O—C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R7 is independently C1-6 alkyl, C1-6 alkenyl, C3-7 cycloalkyl, —C(O)—C1-6 alkyl, —C(O)O-C1-6 alkyl, aryl, heteroaryl or heterocyclyl;
- each R8 is independently halo, C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, C3-7 cycloalkyl, C1-6 alkyl-amine, —C(O)—C1-6 alkyl, —C(O)O—C1-6 alkyl, C0-6 alkyl-NHR7, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl or wherein two adjacent R8 moieties, taken together with the atoms to which they are attached, form a C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl group, wherein each alkyl, alkoxy, alkenyl, cycloalkyl, aryl; and
- m, n, o and p are each independently an integer from 0-5.
S—X1 (VI)
with tetramethylethylenediamine and bis(1,5-cyclooctadiene)nickel to provide a nickel complex of formula (VII):
the method further comprising, treating a nickel complex of formula (VII) with a silver compound of formula (VIII) and A2:
to provide a nickel complex of formula (I), wherein Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I) and X1 is a leaving group.
S—B(OR9)2 (X),
with a nickel cubane complex of formula (XI):
-
- Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I); and
- R9 is defined as halo, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C(O)—R6, C(O)OR6, —NH2, —NHR7, —N(R7)2, —OH, —OR6, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl, or heterocyclyl can be further substituted with 0-3 occurrences of R8.
S—B(X1)4M1 (XIII),
with a nickel cubane complex of formula (XI):
-
- Ar1, Ar2, A1, A2, A3, R1, R2, R3, R4, R6, R7, R8, m, n, o and p are as defined for formula (I);
- X1 is a leaving group; and
- M1 is an alkali metal.
Under air, to 2-bromopyridine (4.54 g, 28.7 mmol, 1.00 equiv) in DME—H2O (1:1, 100 mL) at 23 ° C. was added K2CO3 (5.96 g, 43.1 mmol, 1.50 equiv), 2-aminophenylboronic acid pinacol ester (6.30 g, 28.7 mmol, 1.00 equiv), and tetrakis(triphenylphosphine)palladium (1.66 g, 1.44 mmol, 5.00 mol%). The reaction mixture was stirred at 100 ° C. for 3.0 h. After cooling to 23 ° C., the phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 4:1 (v/v) to afford 4.20 g of the title compound as a red-brown oil (86%). Rf=0.38 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.61-8.60 (m, 1H), 7.78-7.75 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.6 Hz, 1.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.80-6.76 (m, 2H), 5.72 (br s, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 159.5, 147.9, 146.6, 136.9, 129.9, 129.4, 122.2, 122.2, 121.0, 117.6, 117.2.
To silver(I) oxide (4.99 g, 21.5 mmol, 0.500 equiv) in CH3CN (200 mL) at 23 ° C. was added 2-(2-pyridinyl)phenyl-2-nitrobenzenesulfonanilide (S2) (15.3 g, 43.1 mmol, 1.00 equiv). After stirring for 12 h at 65 ° C., the resulting light gray solid was collected on a frit and in vacuo to afford 18.3 g of the title compound as a light gray solid (92%). Anal: calcd for C17H12AgN3O4S: C, 44.17; H, 2.62; N, 9.09; found: C, 44.06; H, 2.66; N, 9.00. The 1H and 13C NMR spectra are not obtained due to a poor solubility.
Based on a reported procedure: All manipulations were carried out in a dry box under a N2 atmosphere. To (diacetoxyiodo)benzene (3.00 g, 9.31 mmol, 1.00 equiv) dissolved in CH2C1 2 (100 mL) in a round-bottom flask was added TMSOTf (4.14 g, 18.6 mmol, 2.00 equiv) dropwise over 1 minute at 23 ° C. 4-Methoxypyridine (2.03 g, 18.6 mmol, 2.00 equiv) in CH2C1 2 (15 mL) was added to the solution dropwise over 5 minutes. The reaction mixture was concentrate until a white solid was observed. To the reaction mixture was added 100 mL of Et2O and the resulting solid was collected on a frit. The solid was washed with Et2O (3 x 10 mL) and subsequently dried under vacuum to afford 6.52 g of the title compound as a colorless solid (97%). NMR Spectroscopy: c 1H NMR (500 MHz, CD3CN, 23 ° C., δ): 8.77 (d, J=7.5 Hz, 4H), 8.60 (d, J=8.5 Hz, 2H), 7.79 (t, J=7.5 Hz, 1H), 7.64 (t, J=8.5 Hz, 2H), 7.19 (d, J=7.5 Hz, 4H), 3.99 (s, 3H). 13C NMR (125 MHz, CD3CN, 23 ° C., δ): 172.1, 149.9, 136.1, 135.7, 134.2, 121.9 (q, J=319 Hz, triflate), 115.3, 58.5. 19F NMR (375 MHz, CD3CN, 23 ° C., δ): −77.5. Anal: calcd for C20H19F6IN2O8S2: C, 33.34; H, 2.66; N, 3.89; found: C, 33.05; H, 2.59; N, 3.73.
To a solution of tetramethylethylenediamine (TMEDA, 0.107mL, 0.717 mmol, 1.00 equiv) and aryl bromide (0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 15 min to 3 h depending on aryl bromides. Pentane (16 mL) was added to the mixtures and the corresponding nickel complexes were collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (1.00 equiv) and nickel(II) aryl or alkenyl bromide complex (7a-7l, 200 mg, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was concentrated and the residual solid was triturated with 20 mL of pentane and collected on a frit. The solid was extracted with CH2C1 2 (5 mL) and the solution was filtered through a pad of Celite on a glass frit and the filtered cake was extracted further with dichloromethane (3×1 mL). The combined filtrate was concentrated in vacuo and the resulting residue was redissolved in dichloromethane and the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resulting residue was purified by recrystallization (CH2Cl2/pentane) or chromatography on silica gel.
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 4-bromobiphenyl (0.167 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 2 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.288 g of the title compound as an orange solid (99%). Anal: calcd for C18H25BrN2Ni: C, 52.99; H, 6.18; N, 6.87; found: C, 52.69; H, 6.16; N, 6.84.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.227 g, 0.490 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7a) (0.200 g, 0.490 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (78.0 mg, 79.0 μL, 0.980 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was redissolved in dichloromethane (8 mL) and the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resulting residue was recrytallized by dissolving the solid in CH2Cl2 (3 mL) and layering with pentane (17 mL). After one hour, the solid was collected by filtration to afford 0.256 g of the title compound as a yellow solid (81%). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, δ): 9.17 (d, J=5.4 Hz, 2H), 8.25 (d, J=5.4 Hz, 1H), 7.57-7.47 (m, 6H), 7.43-7.36 (m, ), 7.32-7.28 (m, 3H), 7.21-6.97 (m, 10H), 6.61-6.59 (m, 1H). 13C NMR (125 MHz, CDCl3, δ): 156.0, 154.9, 152.7, 151.4, 147.0, 141.6, 141.2, 137.2, 136.7, 136.5, 135.8, 135.6, 135.5, 131.6, 130.4, 130.2, 129.9, 128.7, 128.6, 128.3, 126.6, 126.4, 124.4, 124.3, 124.2, 122.8, 122.6, 121.8. Anal: calcd for C34H26N4NiO4S: C, 63.28; H, 4.06; N, 8.68; found: C, 63.02; H, 4.31; N, 8.48.
To a solution of TMEDA (0.133 mL, 0.896 mmol, 1.00 equiv) and 2-bromofluorene (0.220 g, 0.896 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.250 g, 0.896 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 2 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.348 g of the title compound as a pink solid (92%). Anal: calcd for C19H25BrN2Ni: C, 54.33; H, 6.00; N, 6.67; found: C, 53.98; H, 5.85; N, 6.56.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.110 g, 0.238 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7b) (0.100 g, 0.238 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (37.7 mg, 38.4 μL, 0.476 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (0.5 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×3 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) and recrystallized with CH2Cl2/pentane and recrystallized with CH2Cl2/pentane to afford 0.148 g of the title compound as a yellow solid (95%). Rf=0.53 (hexanes/EtOAc 1:2 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 9.18 (d, J=5.3 Hz, 2H), 8.24 (d, J=6.4 Hz, 1H), 7.65 (s, 1H), 7.58-7.46 (m, 6H), 7.40-7.37 (m, 2H), 7.29-7.21 (m, 3H), 7.16-7.07 (m, 6H), 7.02-6.97 (m, 2H), 6.57-6.54 (m, J=6.3, 1H), 3.72-3.58 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 156.0, 155.2, 152.6, 151.4, 147.0, 142.6, 142.2, 141.3, 141.0, 137.1, 137.1, 136.7, 136.6, 135.6, 133.0, 131.8, 131.6, 130.4, 130.2, 129.9, 128.7, 128.3, 126.5, 125.6, 124.9, 124.4, 124.1, 122.8, 122.7, 121.7, 118.9, 117.1, 36.4. Anal: calcd for C35H26N4NiO4S·(CH2Cl2)0.1: C, 63.31; H, 3.97; N, 8.41; found: C, 63.04; H, 4.18; N, 8.36.
To a solution of TMEDA (0.157 mL, 1.05 mmol, 1.00 equiv) and tert-butyl 5-bromoindole-1 -carboxylate (0.311 g, 1.05 mmol, 1.00 equiv) in toluene (5 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.293 g, 1.05 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 3 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.491 g of the title compound as a peach solid (99%). Anal: calcd for C19H30BrN3NiO2: C, 48.44; H, 6.42; N, 8.92; found: C, 48.14; H, 6.22; N, 8.84.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.0980 g, 0.212 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7c) (0.100 g, 0.212 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (3 mL) that contained pyridine (33.6 mg, 34.2 μL, 0.425 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (0.5 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×3 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) and recrystallized with CH2Cl2/pentane to afford 0.140 g of the title compound as a yellow solid (93%). Rf=0.53 (hexanes/EtOAc 1:2 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 9.10 (d, J=4.3 Hz, 2H), 8.16 (d, J=5.3 Hz, 1H), 7.59-7.39 (m, 6H), 7.33-7.29 (m, 2H), 7.21-7.18 (m, 2H), 7.09-7.00 (m, 5H), 6.93-6.91 (m, 2H), 6.48-6.47 (m, 1H), 6.23 (d, J=4.3, 1H), 1.50 (s, 9H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 156.0, 152.7, 151.5, 150.1, 147.0, 146.8, 141.3, 137.0, 136.6, 136.6, 135.7, 131.6, 130.7, 130.4, 130.1, 129.9, 129.3, 128.8, 128.3, 126.7, 124.4, 124.3, 124.1, 122.8, 122.6, 121.7, 112.6, 83.1, 28.0. Anal: calcd for C35H31N5NiO6S·(CH2Cl2)0-1: C, 58.81; H, 4.39; N, 9.77; found: C, 58.49; H, 4.39; N, 9.81. X-ray quality crystals were obtained from 2 mL CH2Cl2 solution that contained 10.0 mg of the title compound slowly layered with 8.0 mL pentane at 23 ° C. (See
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 4-bromobenzophenone (0.187 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(O) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 15 min. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.305 g of the title compound as an orange solid (98%). Anal: calcd for C19H25BrN2NiO·(PhMe)0.1: C, 53.15; H, 5.84; N, 6.29; found: C, 53.41; H, 5.84; N, 6.18.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.212 g, 0.459 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7d) (0.200 g, 0.459 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (78.0 mg, 79.0 μL, 0.980 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) and recrystallized with CH2Cl2/pentane to afford 0.138 g of the title compound as a yellow solid (45%).
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 1-bromo-2-cyclohexylbenzene (0.171 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 3 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.208 g of the title compound as a pink solid (70%). Anal: calcd for C18H31BrN2Ni: C, 52.21; H, 7.55; N, 6.77; found: C, 51.87; H, 7.43; N, 6.73.
To a mixture of 2-(4-bromophenyl)ethanol (1.00 g, 4.97 mmol, 1.00 equiv) and Et3N (0.763 ml, 0.554 g, 5.47 mmol, 1.10 equiv) in a round-bottom flask in THF (20 ml) was added benzoyl chloride (0.589 mL, 0.713 g, 5.07 mmol, 1.02 equiv). The reaction mixture was stirring for 4 h at 23 ° C. and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 1.50 g of the title compound as a colorless solid (99%). Rf=0.7 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.00 (d, J=7.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.45-7.42 (m, 4H), 7.16 (d, J=8.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.04 (t, J=6.4 Hz, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 166.6, 137.1, 133.1, 131.8, 130.8, 130.3, 129.7, 128.5, 120.6, 65.2, 34.8.
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 4-bromophenethyl benzoate (0.219 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 1.5 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.208 g of the title compound as an orange-pink solid (90%). Anal: calcd for C21H29BrN2NiO2: C, 52.54; H, 6.09; N, 5.84; found: C, 52.81; H, 5.95; N, 5.53.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.193 g, 0.417 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7f) (0.200 g, 0.417 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (65.9 mg, 67.1 μL, 0.833 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) to afford 0.152 g of the title compound as a yellow solid (51%).
To 3-pinacolatoboroestra-1,3,5-(10)-triene-17-one (3.50 g, 9.20 mmol, 1.00 equiv) in a round-bottom flask in MeOH (70 ml) was added copper(II) bromide (11.0 g, 49.2 mmol, 5.00 equiv) in H2O (70 mL) in one portion. The reaction mixture was stirring under reflux at 110 ° C. for 3 d. The reaction mixture was cooled to 23 ° C. and was poured into H2O (200 mL). A white precipitate was collected on a frit, followed by washing with water (3×30 mL). CH2Cl2 (100 mL) was added to the solid and the solution was filtered though a pad of Celite. The filtrate was concentrated, triturated with Et2O (3×5 mL) and dried to afford 2.60 g of the title compound as a colorless solid (85% yield).
To a solution of TMEDA (0.134 mL, 0.896 mmol, 1.00 equiv) and 3-deoxy-3-bromoestrone (0.299 g, 0.896 mmol, 1.00 equiv) in toluene (5 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.896 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 2 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.406 g of the title compound as a peach solid (89%). Anal: calcd for C24H37BrN2NiO: C, 56.73; H, 7.34; N, 5.51; found: C, 52.92; H, 6.91; N, 5.50. Numerous attempts were made to get elemental analysis data satisfactory one was not obtained. However, purification by chromatography on next step enables to access pure 1 g.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.193 g, 0.417 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7g) (0.200 g, 0.417 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (65.9 mg, 67.1 μL, 0.833 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) and recrystallized with CH2Cl2/pentane to afford 0.152 g of the title compound as a yellow solid (51%). Rf=0.35 (hexanes/EtOAc 1:2 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 9.14 (d, J=4.9 Hz, 2H), 8.28-8.26 (m, 1H), 7.54-7.45 (m, 4H), 7.36-7.28 (m, 2H), 7.16-6.97 (m, 9H), 6.66-6.62 (m, 2H), 2.77-2.60 (m, 2H), 2.47-2.41 (m, 2H), 2.21-1.85 (m, 6H), 1.55-1.27 (4H), 0.82 (m, 3H). 13C NMR (125 MHz CDCl3, 23 ° C., δ): 221.3, 156.0, 152.7, 152.7, 151.5, 150.7, 150.6, 147.0, 141.3, 137.0, 136.6, 135.9, 135.8, 135.7, 133.9, 133.8, 133.7, 133.1, 132.9, 131.6, 131.3, 130.5, 130.4, 130.1, 129.7, 128.8, 128.4, 128.3, 124.4, 124.2, 124.1, 122.8, 122.7, 122.7, 122.6, 121.7, 50.7, 48.2, 44.2, 44.2, 38.4, 38.3, 36.0, 31.8, 29.5, 29.5, 26.9, 25.6, 25.6, 21.7, 14.0. Anal: calcd for C40H38N4NiO5S·(CH2Cl2)0.1: C, 63.88; H, 5.11; N, 7.43; found: C, 63.62; H, 5.26; N, 7.06.
To 5-bromo-2-hydroxybenzaldehyde (1.00 g, 4.97 mmol, 1.00 equiv) and K2CO3 (3.44 g, 24.9 mmol, 5.00 equiv) in THF (10 mL) in an oven-dried round-bottom flask fitted with a reflux condenser under a N2 atmosphere at 23 ° C. was added (bromomethyl)cyclopropane (1.01 g, 0.724 mL, 7.46 mmol, 1.50 equiv). The reaction mixture was warmed in an oil heating bath at a temperature of 70 ° C. and heated at reflux with vigorous stirring for 40 hours. The reaction mixture was cooled to 23 ° C. and poured into H2O (30 mL) in a separatory funnel. CHCl3 (30 mL) was added, the funnel was shaken and the organic phase collected. The aqueous phase was then extracted with CHCl3 (2×30 mL). The combined organic phases were washed with brine (30 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 2-7% EtOAc in hexanes (v/v) to afford 1.05 g of the title compound as a colorless solid (83% yield). Rf=0.30 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (600 MHz, CDCl3, 23 ° C., δ): 10.45 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.9, 2.6 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 3.91 (d, J=7.2 Hz, 2H), 1.32-1.26 (m, 1H), 0.71-0.63 (m, 2H), 0.41-0.34 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 188.7, 160.5, 138.3, 130.9, 126.5, 115.0, 113.5, 73.9, 10.1, 3.4. HRMS-FIA (m/z): calcd for C11H11BrNaO2[M+Na]+, 276.9840; found, 276.9820.
To 5-bromo-2-(cyclopropylmethoxy)benzaldehyde (S5) (3.10 g, 12.2 mmol, 1.00 equiv) and LiCl (0.541 g, 12.8 mmol, 1.05 equiv) in MeCN (45 mL) in a round-bottom flask under a N2 atmosphere at 0 ° C. was added triethyl phosphonoacetate (3.00 g, 2.68 mL, 13.4 mmol, 1.10 equiv) and 1,8-diazabicycloundec-7-ene (DBU) (2.04 g, 2.02 mL, 13.4 mmol, 1.10 equiv). Upon the addition of DBU, the reaction mixture turned yellow. The reaction mixture was warmed to 23 ° C. and stirred for 15 hours. The reaction mixture was poured into H2O (75 mL) in a separatory funnel. CHCl3 (75 mL) was added and the funnel was shaken and the organic phase collected. The aqueous phase was extracted from with CHCl3 (2×50 mL). All organic phases were combined and washed with brine (50 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5-10% EtOAc in hexanes (v/v) to afford 3.89 g of the title compound as a colorless solid (98% yield). Rf=0.25 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.93 (d, J=16.1 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.37 (dd, J=8.8, 2.5 Hz, 1H), 6.74 (d, 8.8 Hz, 1H), 6.53 (d, J=16.1 Hz, 1H), 4.26 (q, J=6.8 Hz, 2H), 3.84 (d, J=6.8 Hz, 2H), 1.34-1.25 (m, 4H), 0.70-0.61 (m, 2H), 0.40-0.31 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 167.3, 156.9, 138.7, 133.7, 131.3, 125.9, 120.0, 114.4, 113.0, 73.9, 60.6, 14.4, 10.2, 3.4. HRMS-FIA (m/z): calcd for C15H18BrO3 [M+]+, 325.0439; found, 325.0428.
To (E)-ethyl 3-(5-bromo-2-(cyclopropylmethoxy)phenyl)acrylate (S6) (3.78 g, 11.6 mmol, 1.00 equiv) in PhMe (30 mL) in a flame-dried round-bottom flask under a N2 atmosphere at −78 ° C. was added a 1.0 M solution of diisobutylaluminum hydride (DIBAL-H) in PhMe (26 mL, 26 mmol, 2.2 equiv) in 6 portions dropwise every 10 minutes for 1 hour. The reaction was warmed to 0 ° C. over 2 hours and then warmed to 23 ° C. and stirred at this temperature for 1 hour. The reaction mixture was poured onto a concentrated aqueous Rochelle's salt (potassium sodium tartrate) solution (400 mL). EtOAc (400 mL) was added and the mixture was stirred for 3 hour until two liquid phases separated cleanly. The phases were partitioned and the aqueous phase was extracted from with EtOAc (300 mL). The organic phases were combined and washed with brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 10-25% EtOAc in hexanes (v/v) to afford 2.77 g of the title compound as a colorless solid (84% yield). Rf=0.15 (hexanes/EtOAc 6:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.53 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.8, 2.4 Hz, 1H), 6.88 (d, J=16.1 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.39 (dt, J=16.1, 5.9 Hz, 1H), 4.33 (br dd, J=4.6, 4.6 Hz, 2H), 3.79 (d, J=6.8 Hz, 2H), 1.71 (br t, J=5.1 Hz, 1H), 1.31-1.23 (m, 1H), 0.68-0.58 (m, 2H), 0.38-0.30 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 155.4, 131.2, 130.5, 129.7, 128.2, 125.0, 114.2, 113.2, 73.7, 64.1, 10.3, 3.4. HRMS-FIA (m/z): calcd for C13H15BrNaO2 [M+Na]+, 305.0153; found, 305.0123.
Following a published procedure for asymmetric allylic cyclopropanation: To dimethoxyethane (DME) (1.39 g, 1.60 mL, 15.4 mmol, 1.90 equiv) in CH2Cl2 (50 mL) in a flame-dried round-bottom flask under a N2 atmosphere cooled in an ethyleneglycol/CO2 bath at −15 ° C. was added diethylzinc (2.01 g, 1.67 mL, 16.3 mmol, 2.00 equiv), while maintaining the bath temperature between −15 and −10 ° C. CH2I2 (8.70 g, 2.62 mL, 32.5 mmol, 4.00 equiv) was added dropwise over 20 minutes at −15 ° C. The reaction mixture was stirred at −15 ° C. for 10 minutes. A solution of (4R,5R)-2-butyl-N,N,N′,N′-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide (2.63 g, 2.46 mL, 9.75 mmol, 1.20 equiv) in CH2Cl2 (10 mL) from a separate flame-dried round-bottom flask under a N2 atmosphere was added over 5 minutes via syringe. A solution of (E)-3-(5-bromo-2-(cyclopropylmethoxy)phenyl)prop-2-en-1-ol (S7) (2.30 g, 8.12 mmol, 1.00 equiv) in CH2Cl2 (10 mL) from a separate flame-dried round-bottom flask under a N2 atmosphere was added over 5 minutes via syringe. The reaction mixture was allowed to warm to 23 ° C. and stirred for 20 hours. Saturated aqueous NH4Cl solution (10 mL) and 1M HC1 (50 mL) were added to the reaction mixture. The reaction mixture was transferred to a separatory funnel. Diethyl ether (200 mL) was added and the separatory funnel was shaken and the organic phase was separated. The aqueous phase was extracted from with diethyl ether (200 mL) and then again with diethyl ether (100 mL). The combined organic phases were transferred to an Erlenmeyer flask. 2 M NaOH solution (60 mL) and 30% H2O2 solution (15 mL) were added. The reaction mixture was stirred vigorously for 5 minutes. The reaction mixture was transferred into a separatory funnel and partitioned. The organic phase was washed with 1.0 M aqueous HC1 (75 mL), saturated aqueous Na2CO3 solution (75 mL), saturated aqueous NaHCO3 solution (75 mL) and brine (75 mL). The organic phase was dried with MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 10-30% EtOAc in hexanes (v/v) to afford 2.21 g of the title compound as a colorless oil (92% yield and 96% ee as determined on a Chiracel ODH column with 5% isopropanol/hexanes eluent (see
To ((1S,2S)-2-(5-bromo-2-(cyclopropylmethoxy)phenyl)cyclopropyl)methanol (S8) (2.15 g, 7.23 mmol, 1.00 equiv) in CH2Cl2 (30 mL) in an oven-dried round-bottom flask under a N2 atmosphere at 0 ° C. was added Et3N (2.20 g, 3.03 mL, 21.7 mmol, 3.00 equiv) and MsCl (1.66 g, 1.13 mL, 14.5 mmol, 2.00 equiv). The reaction mixture was stirred at 0 ° C. for 2 hours. The reaction mixture turned yellow and a precipitate formed. The reaction mixture was poured into a separatory funnel with saturated NH4Cl solution (40 mL). The funnel was shaken and the organic phase collected. The aqueous phase was extracted from with diethyl ether (3×75 mL). The organic phases were combined and washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried with MgSO4, and concentrated in vacuo. The residue was dissolved in DMF (30 mL) and NaN3 (1.88 g, 28.9 mmol, 4.00 equiv) was added. The reaction mixture was heated at 60 ° C. for 1 hour. The reaction mixture was cooled and poured into 60 mL of water. The reaction mixture was extracted from with diethyl ether (3×75 mL). The combined organic phases were washed with brine (100 mL), dried with MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 5-10% EtOAc in hexanes (v/v) to afford 1.95 g of the title compound as a colorless oil (84% yield). Rf=0.60 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.21 (dd, J=8.7, 2.3 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.84-3.78 (m, 2H), 3.40 (dd, J=12.8, 6.4, 1H), 3.24 (dd, J=12.8, 7.1 Hz, 1H), 2.11 (ddd, J=8.7, 5.0, 5.0 Hz, 1H), 1.38-1.32 (m, 1H), 1.31-1.25 (m, 1H), 1.08-1.04 (m, 1H), 0.98-0.94 (m, 1H), 0.68-0.58 (m, 2H), 0.40-0.31 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 156.9, 132.8, 129.5, 128.8, 113.4, 112.9, 73.3, 55.3, 20.8, 16.2, 12.8, 10.4, 3.3, 3.2. HRMS-FIA (m/z): calcd for C14H16BrN3NaO [M+Na]+, 344.0374; found, 344.0363.
To 2-((1S,2S)-2-(azidomethyl)cyclopropyl)-4-bromo-1-(cyclopropylmethoxy)benzene (S9) (1.90 g, 5.90 mmol, 1.00 equiv) in a round-bottom flask open to air in a 2:1 solution of dioxane:H2O (45 mL) cooled to 0 ° C. was added tin(II) chloride (5.59 g, 29.5 mmol, 5.00 equiv). The reaction mixture was allowed to warm to 23 ° C. and stirred for 15 hours. Saturated aqueous NaHCO3 solution (50 mL) was carefully added. The addition was accompanied by foaming. H2O (15 mL) was added followed by Boc2O (3.86 g, 4.11 mL, 17.7 mmol, 3.00 equiv). The reaction mixture was stirred for 3 hours and then transferred to a separatory funnel. The reaction mixture was extracted from with EtOAc (3×75 mL). The combined organic phases were washed with brine (75 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 5-20% EtOAc in hexanes (v/v) to afford 1.96 g of the title compound as a colorless solid (85% yield). The enantioenriched product could be recrystallized by suspending the solid in hexanes (10 mL), heating the suspension to reflux to dissolve the solid, cooling the solution, and collecting the solid by filtration, affording the title compound in >99% ee as determined on a Chiracel ODH column with 5% isopropanol/hexanes eluent (see
To a solution of TMEDA (0.0537 mL, 0.358 mmol, 1.00 equiv) and t-butyl (((1S,2S)-2-(5-bromo-2-(cyclopropylmethoxy)phenyl)cyclopropyl)methyl) carbamate (S10) (0.142 g, 0.358 mmol, 1.00 equiv) in toluene (3 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.358 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 45 min. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.183 g of the title compound as a peach solid (89%).
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.113 g, 0.245 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7h) (0.140 g, 0.245 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (3 mL) that contained pyridine (38.8 mg, 39.5 L, 0.490 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (0.5 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) recrystallized with CH2C1 2/pentane to afford 75.0 mg of the title compound as a yellow solid (38%).
(S)-N-(tert-butyloxycarbonyl)-2-bromo-4,5-dihydroxyphenylalanine methyl ester was prepared by a published method. To the mixture of (S)-N-(tert-butyloxycarbonyl)-2-bromo -4,5-dihydroxyphenylalanine methyl ester (8.00 g, 20.5 mmol, 1.00 equiv) and Et3N (5.72 ml, 4.15 g, 164 mmol, 2.00 equiv) in a round-bottom flask in PhMe (100 ml) was added Boc2O (3.86 g, 4.11 mL, 17.7 mmol, 3.00 equiv) in one portion. The reaction mixture was stirring under nitrogen atmosphere at 80 ° C. for 9 h. The reaction mixture was cooled to 23 ° C. and was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 30% EtOAc in hexanes (v/v) to afford 11.5 g of the title compound as a light yellow solid (95% yield). Rf=0.53 (hexanes/EtOAc 2:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.46 (s, 1H), 7.11 (s, 1H), 5.10 (d, J=8.4 Hz, 1H), 4.61-4.57 (m, 1H), 3.68 (s, 3H), 3.25-3.20 (m, 1H), 3.11-3.06 (m, 1H), 1.51 (s, 18H), 1.37 (s, 9 H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 172.2, 155.0, 150.3, 141.8, 141.7, 134.6, 127.2, 125.3, 120.8, 84.3, 84.1, 80.1, 53.3, 52.5, 38.2, 28.3, 27.6, 27.5.
To a solution of TMEDA (0.161 mL, 1.08mmol, 1.00 equiv) and N-(tert-butoxycarbonyl) -3,4-di(tert-butoxycarbonyloxy)-6-bromo-L-phenylalaninemethyl ester (S11) (0.635 g, 1.08 mmol, 1.00 equiv) in toluene (8 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.300 g, 1.08 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.735 g of the title compound as a red solid (92%). Anal: calcd for C31H52BrN3NiO10·(PhMe)0.2: C, 49.65; H, 6.89; N, 5.36; found: C, 49.29; H, 6.65; N, 4.74.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (7) (0.302 g, 0.650 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (6i) (0.500 g, 0.650 mmol, 1.00 equiv) in a round-bottom flask was added an toluene solution (8 mL) that contained pyridine (103 mg, 105 μL, 1.31 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (2.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:3 (v/v) (0.5% Et3N) to afford 0.260 g of the title compound as a yellow solid (40%). Rf=0.40 (hexanes/EtOAc 1:2 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CD2Cl2, 23 ° C., δ): 9.04 (d, J=4.9 Hz, 2H), 8.32 (d, J=5.4 Hz, 0.4H), 8.26 (d, J=5.4 Hz, 0.6H), 8.05 (s, 1H), 7.66-7.32 (m, 7H), 7.27-7.15 (m, 5H), 7.08-7.01 (m, 4H), 6.73-6.63 (m, 1H), 6.40 (s, 0.6H), 6.32 (s, 0.4H), 4.35-4.22 (m, 1H), 4.07-3.93 (m, 1H), 3.88-3.80 (m, 2H), 3.54-3.41 (m, 3H), 1.59 (s, 5H), 1.58 (s, 5H), 1.44 (s, 9H), 1.31 (s, 8H). 13C NMR (125 MHz CD2Cl2, 23 ° C., δ): 173.2, 156.2, 155.3, 154.5, 151.8, 151.5, 151.4, 147.2, 140.8, 140.7, 139.7, 139.5, 139.3, 138.3, 138.0, 137.6, 137.5, 136.6, 136.3, 135.8, 132.0, 130.9, 130.8, 130.2, 129.1, 129.1, 128.6, 127.9, 127.8, 124.8, 124.7, 124.6, 123.6, 123.0, 122.7, 122.5, 119.4, 119.2, 83.5, 83.4, 79.8, 54.6, 52.3, 40.8, 28.4, 28.1, 27.9, 27.7. Note: Conformational isomers were observed in 1H NMR spectrum. Fractional hydrogen integration is possibly due to slow rotation about bonds as seen for similar complexes. Anal: calcd for C47H53N5NiO14S: C, 56.30; H, 5.33; N, 6.98; found: C, 55.98; H, 5.18; N, 6.90.
To a solution of TMEDA (83.0 mg, 0.107 mL, 0.717 mmol, 1.00 equiv) and 3-bromobenzamide (143 mg, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added Ni(COD)2 (200 mg, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 6 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 225 mg of the title compound as a pink solid (84%). Anal: calcd for C13H22BrN3NiO: C, 41.64; H, 5.91; N, 11.21; found: C, 41.36; H, 5.78; N, 10.95.
To (2-(2-pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (247 mg, 0.533 mmol, 1.00 equiv) and nickel aryl bromide complex (7j) (200 mg, 0.533 mmol, 1.00 equiv) in a 20 mL vial was added a toluene solution (4 mL) that contained pyridine (84.0 mg, 86.0 μL, 1.07 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with EtOAc and further recrystallized by dissolving the columned solid in CH2Cl2 (2 mL) and layering with pentane (20 mL) to afford 154 mg of the title compound as a yellow solid (47%). Rf=0.26 (EtOAc). NMR Spectroscopy: 1H NMR (500 MHz, CD2Cl2, 23 ° C., δ): 9.13 (d, J=4.9 Hz, 2H), 8.15 (d, J=5.4 Hz, 1H), 7.86 (s, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.63-7.56 (m, 3H), 7.42-7.32 (m, 3H), 7.23-7.17 (m, 4H), 7.08-7.02 (m, 4H), 6.87-6.84 (m, 1H), 6.64- 6.61 (m, 1H), 5.94 (br s, 1H), 5.32 (br s, 1H). 13C NMR (125 MHz CD2Cl2, 23 ° C., δ): 157.1, 156.2, 152.5, 151.5, 147.3, 141.3, 139.5, 137.9, 137.3, 136.7, 136.0, 134.1, 131.7, 130.9, 130.8, 130.2, 128.8, 128.7, 126.0, 124.8, 124.5, 123.4, 123.0, 122.3. Anal: calcd for C29H23N5NiO5S (CH2Cl2)0.25: C, 55.46; H, 3.74; N, 11.05; found: C, 55.22; H, 3.82; N, 11.28.
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 5-bromobenzooxazole (0.142 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 22q h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.260 g of the title compound as a yellow solid (97%). Anal: calcd for C13H20BrN3NiO·(PhMe)0.15: C, 43.64; H, 5.53; N, 10.87; found: C, 43.44; H, 5.29; N, 10.33.
To 4-bromobenzoic acid (5.00 g, 24.9 mmol, 1.00 equiv) and N-hydroxysuccinimide (3.66 g, 31.8 mmol, 1.28 equiv) in a round-bottom flask in dioxane (120 mL) was added an dioxane solution (30 mL) that contained 1,3-dicyclohexylcarbodiimide (DCC) (6.77 g, 32.8 mmol, 1.32 equiv) dropwise over 5 min at 23 ° C. The reaction mixture was stirring at 23 ° C. for 24 h. The reaction mixture was concentrated in vacuo and the crude product was obtained by recrystallization in a cold acetone. The crude product was further purified by chromatography on silica gel eluting with hexanes/EtOAc 2:1 (v/v) to afford 6.34 g of the title compound as a colorless solid (86%).
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and 4-bromobenzoic acid succinimidyl ester (S12) (0.214 g, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 1.5 h. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.300 g of the title compound as an orange solid (89%). Anal: calcd for C17H24BrN3NiO4: C, 43.17; H, 5.11; N, 8.88; found: C, 43.65; H, 4.54; N, 7.48.
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.195 g, 0.423 mmol, 1.00 equiv) and nickel(II) aryl bromide complex (7k) (0.200 g, 0.423 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (4 mL) that contained pyridine (66.9 mg, 68.1 L, 0.833 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (1.0 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) to afford 0.152 g of the title compound as a yellow solid (51%). Rf=0.47 (hexanes/EtOAc 1:6 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 9.10 (d, J=5.2 Hz, 2H), 8.05 (d, J=5.6 Hz, 1H), 7.7 (d, J=7.9 Hz, 2H), 7.58-7.54 (m, 3H), 7.47-7.32 (m, 5H), 7.19-7.11 (m, 4H), 7.05-6.97 (m, 3H), 6.63-6.61 (m, 1H), 2.81 (s, 4H). 13C NMR (125 MHz CDCl3, 23 ° C., δ): 174.2, 169.7, 162.9, 155.9, 152.3, 151.2, 147.0, 140.9, 137.6, 137.1, 136.4, 136.0, 135.4, 131.8, 130.5, 130.4, 130.1, 128.6, 128.4, 126.4, 124.6, 124.4, 122.9, 122.8, 122.0, 119.5, 25.7. Anal: calcd for C33H25N5NiO8S: C, 55.80; H, 3.55; N, 9.86; found: C, 55.53; H, 3.50; N, 9.61.
To a solution of TMEDA (0.107 mL, 0.717 mmol, 1.00 equiv) and bromotriphenylethylene (0.240 mg, 0.717 mmol, 1.00 equiv) in toluene (4 mL) was added bis(cyclooctadiene)nickel(0) (Ni(COD)2, 0.200 g, 0.717 mmol, 1.00 equiv), and the mixture was stirred at room temperature for 40 min. Pentane (16 mL) was added to the mixtures and the resulting solid was collected on a frit. The solid was washed with pentane (3×5 mL) and dried in vacuo to afford 0.305 g of the title compound as a pink solid (86%). Attempts were made to get elemental analysis data but satisfactory one was not obtained. However, purification by chromatography on next step enables to access pure 1l.
Synthesis of Nickel(II) Alkenyl Complex (1l)
To (2-(2-Pyridinyl)phenyl-2-nitrobenzenesulfonamide)silver(I) (8) (0.0930 g, 0.417 mmol, 1.00 equiv) and nickel(II) alkenyl bromide complex (71) (0.100 g, 0.417 mmol, 1.00 equiv) in a 20 mL vial was added an toluene solution (3 mL) that contained pyridine (32.0 mg, 32.5 μL, 0.833 mmol, 2.00 equiv) at 23 ° C., followed by addition of acetonitrile (0.5 mL). After stirring for 1 min at 23, the solution was filtered through a glass frit and the filtered cake was extracted further with dichloromethane (3×5 mL). The combined filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:2 (v/v) to afford 78.0 mg of the title compound as a yellow solid (52%). Rf=0.66 (hexanes/EtOAc 1:2 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 9.85 (d, J=7.5 Hz, 1H), 8.77-8.60 (m, 3H), 7.80 (d, J=7.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.49-7.30 (m, 6H), 7.24-6.82 (m, 15H), 6.69-6.59 (m, 4H), 6.40 (d, J=7.1 Hz, 1H),. 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 160.7, 156.7, 156.5, 154.6, 152.3, 152.0, 151.9, 151.6, 148.0, 147.9, 147.3, 146.9, 145.2, 143.7, 143.2, 142.4, 141.8, 141.0, 137.4, 136.8, 136.5, 136.2, 135.9, 135.8, 135.2, 131.4, 131.1, 131.0, 130.7, 130.6, 130.3, 130.1, 130.0, 130.0, 129.9, 129.5, 129.4, 129.1, 128.9, 128.7, 128.2, 127.6, 127.5, 127.4, 127.2, 127.0, 127.0, 127.0, 126.5, 125.8, 125.3, 125.0, 124.6, 123.5, 123.4, 123.2, 123.0, 122.8, 122.6, 122.4, 122.0, 121.6. There are more 13C peaks than could be expected, possibly due to slow rotation about bonds as seen for similar complexes. Anal: calcd for C42H32N4NiO4S·(CH2C1 2)0.15: C, 66.59; H, 4.28; N, 7.37; found: C, 66.71; H, 4.24; N, 7.51.
In a glove box under a N2 atmosphere, nickel (II) aryl complex 1a (40 mg, 0.62 mmol, 1.0 equiv), tetrabutylammonium difluorotriphenylsilicate (TBAT) (50 mg, 0.93 mmol, 1.5 equiv), and the oxidant (6) (50 mg, 0.93 mmol, 1.5 equiv) were placed in a 20 mL vial. The vial was taken out of the glove box, and immersed in an ice bath at 0 ° C. for 5 minutes. To the reaction mixture was added quickly pre-cooled acetonitrile (4 mL) at 0 ° C. in one portion and the solution was stirred for 1 min at 0 ° C. After warmed to 23 ° C., the solution was concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with hexane/EtOAc 99:1 (v/v) to afford 6.9 mg of the title compound as a white solid (65% yield). TLC (hexane/EtOAc, 19:1 v/v): RF=0.60;1H—NMR (500 MHz, CDCl3, 23 ° C.): δ7.60-7.54 (m, 4H), 7.47 (dd, J=7.5 Hz, 7.0 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.14 (dd, J=8.0 Hz, 7.5 Hz, 2H); 13C—NMR (125 MHz, CDCl3, 23 ° C.): δ162.7 (d, J=244 Hz), 140.5, 137.6, 129.0, 128.9 (d, J=8.5 Hz), 127.5, 127.3, 115.8 (d, J=21 Hz); 19F—NMR (375 MHz, CDCl3, 23 ° C.): δ—116.2.
Nickel aryl complex 1e (50 mg, 0.077 mmol, 1.0 equiv) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (33 mg, 0.092 mmol, 1.5 equiv) were placed in a 20 mL vial. To the reaction mixture was added acetonitrile (4 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C. The solution was concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with pentane to afford 8.1 mg of the title compound and cyclohexylbenzene as a 1:2 mixture (a colorless oil, 22% yield based on 1-cyclohexyl-2-fluorobenzene). Due to the difficulty of purification of the title compound and its volatility, the above mixture was used without further purification for identifying [18F]2e by HPLC analysis.
Nickel aryl complex 1f (30 mg, 0.042 mmol, 1.0 equiv) and Selectfluor® (18 mg, 0.050 mmol, 1.2 equiv) were placed in a 20 mL vial. To the reaction mixture was added quickly acetonitrile (3 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C. The solution was subsequently concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with hexane/EtOAc 4:1 (v/v) to afford 5.6 mg of the title compound as a colorless solid (55% yield).
To N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-bromo-L-phenylalaninemethyl ester (S11) (1.00 g, 1.69 mmol, 1.00 equiv) in dioxane (20 mL) at 23 ° C. was added lithium chloride (0.359 g, 8.47 mmol, 5.0 equiv), tetrakis(triphenylphosphine)palladium (0.391 g, 0.339 mmol, 20.0 mol%) and bis(trimethyltin) (1.11 g, 3.39 mmol, 2.00 equiv). After stirring for 5 hr at 100 ° C., the reaction mixture was cooled to 23 ° C. and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with hexanes/EtOAc 5:1 (v/v), to afford 420 mg of the title compound as a colorless oil (37% yield). Rf=0.55 (hexane/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.26 (br s, 1H), 7.08 (br s, 1H), 4.89 (d, J=7.6 Hz, 1H), 4.53-4.48 (m, 1H), 3.70 (s, 3H), 3.10-3.00 (m, 2H), 1.54 (s, 9H), 1.53 (s, 9H), 1.39 (s, 9H), 0.35 (s, 9H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 172.7, 155.2, 150.9, 150.8, 142.7, 141.7, 141.5, 141.0, 130.4, 123.4, 110.8, 83.8, 80.2, 54.5, 52.5, 40.4, 28.3, 27.7, 27.7, −7.7. HRMS-FIA (m/z): calcd for C28H45NO10Sn[M+]+, 676.2144; found, 676.2171.
To N-Boc-O-Boc-6-trimethylstannyl-DOPA methyl ester (S13) (142 mg, 0.211 mmol, 1.00 equiv) in acetone (4 mL) at 23 ° C. was added silver oxide (2.45 mg, 0.0106 mmol, 5.0 mol%), sodium bicarbonate (35.5 mg, 0.422 mmol, 2.0 equiv), sodium trifluoromethanesulfonate (36.3 mg, 0.211 mmol, 1.0 equiv) and Selectfluor® (112 mg, 0.317 mmol, 1.50 equiv). The reaction mixture was stirred for 5 hr at 65 ° C. in a sealed vial. After cooling to 23 ° C., the reaction mixture was filtered through a pad of Celite, eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc 4:1 (v/v), to afford 45.0 mg of the title compound as a colorless solid (40% yield).
Nickel aryl complex 1l (30 mg, 0.040 mmol, 1.0 equiv) and Selectfluor® (17 mg, 0.048 mmol, 1.2 equiv) were placed in a 20 mL vial. To the reaction mixture was added quickly acetonitrile (3 mL) at 23 ° C. in one portion and the solution was stirred for 1 min at 23 ° C. The solution was subsequently concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with Et2O/CH2Cl2 2:1 (v/v) to afford 4.0 mg of the title compound as a colorless solid (36% yield). Rf=0.88 (Et2O/CH2Cl2 2:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.39-6.95 (m, 15H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 130.8 (d, J=2.8 Hz), 130.1 (d, J=3.4 Hz), 130.8 (d, J=2.8 Hz), 129.2 (d, J=4.6 Hz), 128.7, 128.3, 128.2, 128.1, 128.1, 128.0, 127.7, 127.6, 127.5, 127.1. 19F NMR (375 MHz, CDCl3, 23 ° C., δ): −101.2.
A 250 ml, 2-neck, glass round-bottomed flask equipped with a teflon stirbar, adapter to a nitrogen line, and a plastic cap, was evacuated under vacuum, flame-dried, and refilled with nitrogen. Nickel acetate tetrahydrate (0.280 g, 1.23 mmol) was added, and the flask was evacuated under vacuum and backfilled with nitrogen. Distilled pyridine (16 ml) was added and the resulting dark blue solution was stirred. 2-Nitro-N-(2-(pyridin-2-yl)phenyl)benzenesulfonamide (0.400 g, 1.13 mmol) was dissolved in distilled pyridine (10 ml), and the resulting solution was added dropwise to the reaction via syringe, followed by a pyridine wash (1×2 ml). The mixture became a greenish-blue, homogeneous solution. In a glovebox, potassium tert-butoxide (0.253 g, 2.26 mmol) was weighed into a 20 ml glass vial, a septum affixed with tape, and removed from the glovebox. Distilled pyridine (7 ml) was added to obtain a homogeneous solution. The solution was added to the nickel reaction mixture dropwise via syringe followed by a pyridine wash (1×1 ml). The mixture became greenish-yellow, and a colorless precipitate formed. The mixture was stirred for 1 h at ambient temperature, and the mixture was concentrated in vacuo (50 ° C. waterbath). The crude green-orange residue was dried in vacuo over 12 h. To the crude solid was added 10 ml THF, and the solution was filtered through Celite. The flask was rinsed (2×3 ml THF) and transferred to the filter pad successively. A turbid green solution was obtained. This solution was filtered through a second pad of Celite, rinsing with THF (1×2 ml) to obtain a homogeneous green solution. Water (0.1 ml) was added with vigorous stirring, effecting precipitation of a large amount of turquoise solid and a yellow supernatant. Additional water (0.4 ml) was added with stirring, and the entire mixture was transferred to a 20 ml glass vial with a THF wash (1×1 ml). The mixture was centrifuged, and the yellow supernatant was decanted leaving a turquoise solid. THF (6 ml) was added, the solution was mixed and centrifuged, and the colorless supernatant decanted. The process was repeated once further, and the remaining turquoise solid was dried in vacuo to afford a crude turquoise powder. The powder was suspended in dichoromethane (30 ml) in a 50 ml round-bottom flask, which was sealed and heated at 40 ° C. for 5 min, then filtered through Celite, affording a homogenous green filtrate that was allowed to stand at ambient temperature overnight. The mixture was filtered through Celite to afford a homogeneous green filtrate. Hexanes (12 ml) was added dropwise to the mixture with vigorous stirring. After several minutes, a green precipitate formed. The flask was sealed and placed in a freezer for 8 h, following which time the mixture was centrifuged, and the supernatant decanted. The remaining solid was treated with pentane (10 ml), and the mixture was centrifuged, and the pentane decanted to yield the title compound 1x as a green powder (175 mg, 35%).
To a 4 ml glass vial was added nickel acetate tetrahydrate (35 mg, 0.14 mmol), a Teflon stirbar, and distilled pyridine (1.4 ml). The vial was capped and the solution stirred vigorously to afford a blue solution. A solution of 2-nitro-N-(2-(pyridin-2-yl)phenyl)benzenesulfonamide (0.050 g, 0.14 mmol) in distilled pyridine (1.4 ml) was added to the reaction mixture dropwise. The resulting dark green-blue solution was stirred for 5 min, whereupon aqueous sodium hydroxide (2.55 M, 0.110 ml) was added dropwise. The mixture was sonicated briefly, leading to a yellow-green solution. Following 20 min, the solution was transferred to a 20 ml glass vial, and pentane (16 ml) was added dropwise with stirring, resulting in a biphasic system. The pentane layer was decanted, and ether (18 ml) was added. The mixture was stirred vigorously, leading to precipitation of a yellow solid. The mixture was centrifuged, the supernatant decanted, and the resulting residue was dried in vacuo. Minimal dicholoromethane was added to the residue, leading to the production of a quantity of orange solid. The mixture was filtered through Celite, affording a green solution that was concentrated in vacuo to afford the product 1x as a green solid (15.6 mg, 6%). An NMR sample was allowed to stand at ambient temperature for 2 days, during which time large green crystals grew. One of these crystals was analyzed by X-ray diffraction (see
To a 20 mL glass vial equipped with a teflon stirbar was added 2,2′-bipyridine(12 mg, 0.077 mmol), 1-(tert-butoxycarbonyl)-1H-indol-5-yl boronic acid (0.020 g, 0.077 mmol), and the nickel complex 1x (34 mg, 0.019 mmol). Dry pyridine (3.1 ml) was added, and the reaction vial was purged with nitrogen and sealed with a cap. The solution was stirred to afford a green mixture with white suspended solid. The reaction was heated to 70 ° C. in an oil bath. Following 30 min, the mixture was cooled to room temperature. The resulting orange solution was concentrated in vacuo to give a brown residue. The solid was triturated with pentane (5×5 ml) and dried in vacuo. The solid was dissolved in dichloromethane, filtered through Celite, reduced in volume to approximately 1 ml in vacuo, following which pentane (15 ml) was added dropwise to the stirred mixture leading to formation of a yellow precipitate. The vial was centrifuged, and the organic layer was decanted. The residual yellow solid was sonicated with pentane (10 ml), centrifuged, the organic layer was decanted, and the process repeated a second time. The residual yellow solid was dried in vacuo to yield the product 1c as a yellow solid (52.0 mg, 96%).
A portion of aqueous [18F]fluoride solution (20-50 μL, 2-5 mCi) obtained from a cyclotron was added to an acetonitrile solution (2.0-5.0 mL) which contained 20 mg of 18-cr-6. The acetonitrile solution (200-500 μl) was added quickly via the septum to the vial (4 mL) that contained 1.0
TABLE S1 |
Radiochemical Yield Data |
RTLC | 18F in | Average | |||
yield | solution | RCY | RCY | ||
Entry | Molecule | (%) | (%) | (%) | (%) |
1 | [18F]2a | 57 | 83 | 47 | 42 |
2 | 68 | 80 | 54 | ||
3 | 49 | 82 | 40 | ||
4 | 48 | 82 | 39 | ||
5 | 49 | 81 | 40 | ||
6 | 38 | 82 | 31 | ||
7 | [18F]2b | 69 | 83 | 58 | 51 |
8 | 61 | 83 | 51 | ||
9 | 52 | 77 | 40 | ||
10 | 47 | 83 | 39 | ||
11 | 73 | 82 | 60 | ||
12 | 69 | 80 | 55 | ||
13 | [18F]2c | 54 | 81 | 44 | 53 |
14 | 72 | 84 | 61 | ||
15 | 72 | 84 | 60 | ||
16 | 64 | 84 | 54 | ||
17 | 57 | 78 | 45 | ||
18 | 69 | 80 | 56 | ||
19 | [18F]2d | 28 | 78 | 22 | 17 |
20 | 18 | 80 | 14 | ||
21 | 19 | 79 | 15 | ||
22 | 19 | 79 | 15 | ||
23 | 24 | 79 | 19 | ||
24 | 21 | 76 | 16 | ||
25 | [18F]2e | 40 | 80 | 32 | 21 |
26 | 24 | 82 | 20 | ||
27 | 21 | 82 | 17 | ||
28 | 25 | 78 | 19 | ||
29 | 26 | 73 | 19 | ||
30 | 26 | 73 | 19 | ||
31 | [18F]2f | 57 | 83 | 47 | 54 |
32 | 57 | 84 | 48 | ||
33 | 54 | 82 | 44 | ||
34 | 72 | 86 | 62 | ||
35 | 78 | 84 | 66 | ||
36 | 75 | 75 | 56 | ||
37 | [18F]2g | 70 | 89 | 62 | 58 |
38 | 66 | 88 | 58 | ||
39 | 76 | 87 | 66 | ||
40 | 66 | 84 | 55 | ||
41 | 61 | 79 | 48 | ||
42 | 72 | 81 | 58 | ||
43 | [18F]2h | 60 | 83 | 50 | 43 |
44 | 66 | 84 | 55 | ||
45 | 52 | 81 | 42 | ||
46 | 44 | 73 | 32 | ||
47 | 42 | 80 | 34 | ||
48 | 56 | 80 | 45 | ||
49 | [18F]2i | 24 | 70 | 17 | 15 |
50 | 22 | 65 | 14 | ||
51 | 41 | 68 | 28 | ||
52 | 14 | 76 | 11 | ||
53 | 17 | 59 | 10 | ||
54 | 13 | 64 | 8 | ||
55 | [18F]2j | 45 | 84 | 38 | 38 |
56 | 53 | 83 | 44 | ||
57 | 51 | 78 | 40 | ||
58 | 51 | 79 | 40 | ||
59 | 33 | 77 | 25 | ||
60 | 49 | 79 | 39 | ||
61 | [18F]2k | 27 | 74 | 20 | 21 |
62 | 30 | 75 | 23 | ||
63 | 34 | 76 | 26 | ||
64 | 32 | 77 | 25 | ||
65 | 21 | 79 | 17 | ||
66 | 20 | 75 | 15 | ||
67 | [18F]2l | 11 | 86 | 9 | 13 |
68 | 14 | 82 | 11 | ||
69 | 15 | 84 | 13 | ||
70 | 14 | 81 | 11 | ||
71 | 20 | 82 | 16 | ||
72 | 17 | 86 | 15 | ||
TABLE S2 |
Effect of Additives on Radiochemical Yield |
Volume | CH3CN + 0.1 | Volume | Entry | Entry | Entry | Entry | |||
of Sat. | mL Crown Ether | of 18 | water | 1 | 2 | 3 | 4 |
| Solution | 10 mg/mL | solution | (%) | RCY (%) | |
|
1 μL | 0.5 |
5 μL | 1.09 | 20.93 | 22.93 | ||
|
1 μL | 0.5 |
5 μL | 1.09 | 45.85 | |||
|
1 μL | 0.5 |
5 μL | 1.09 | 6.23 | 4.16 | ||
K3PO4 | 1 μL | 0.5 |
5 μL | 1.09 | 69.89 | 26.29 | ||
K3PO4 | 2 μL | 0.5 mL | 3.8 μL | 0.95 | 79.93 | 77.9 | 82.6 | 77.3 |
Na2HPO3 | 1 μL | 0.5 |
7 μL | 0.90 | 47.03 | |||
Na2SO4 | 1 μL | 0.5 |
7 μL | 0.90 | 41.4 | |||
Claims (20)
S—X (VI),
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